Antimicrobials methods of making and using the same

ABSTRACT

The present disclosure relates generally to the field of antimicrobial compounds and to methods of making and using them. These compounds are useful for treating, preventing, reducing the risk of, and delaying the onset of microbial infections in humans and animals. In some embodiments, the present disclosure provides a compound of Formula (I) or tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 62/485,811, filed Apr. 14, 2017; 62/444,276, filed Jan. 9, 2017;62/385,722, filed Sep. 9, 2016; and 62/333,012, filed May 6, 2016, allof which are herein incorporated by reference in their entireties.

TECHNICAL FIELD

This invention relates to antimicrobial compounds, and more particularlyto pyrrolo[2,3-d]pyrimidin-2-ones useful for treating, preventing andreducing risk of microbial infections.

BACKGROUND

Since the discovery of penicillin in the 1920s and streptomycin in the1940s, many new compounds have been discovered or specifically designedfor use as antibiotic agents. It was once thought that infectiousdiseases could be completely controlled or eradicated with the use ofsuch therapeutic agents. However, such views have been challengedbecause strains of cells or microorganisms resistant to currentlyeffective therapeutic agents continue to evolve. Almost every antibioticagent developed for clinical use has ultimately encountered problemswith the emergence of resistant bacteria. For example, resistant strainsof Gram-positive bacteria such as methicillin-resistant staphylococci,penicillin-resistant streptococci, and vancomycin-resistant enterococcihave developed. Resistant bacteria can cause serious and even fatalresults for infected patients. See. e.g., Lowry, F. D. “AntimicrobialResistance: The Example of Staphylococcus aureus,” J. Clin. Invest.,vol. 111, no. 9, pp. 1265-1273 (2003); and Gold, H. S. and Moellering,R. C., Jr., “Antimicrobial-Drug Resistance,” N. Engl. J. Med., vol. 335,pp. 1445-53 (1996).

The discovery and development of new antibacterial agents have been fordecades a major focus of many pharmaceutical companies. Nonetheless, inmore recent years there has been an exodus from this area of researchand drug development resulting in very few new antibiotics entering themarket. This lack of new antibiotics is particularly disturbing,especially at a time when bacterial resistance to current therapies isincreasing both in the hospital and community settings.

One approach to developing new antimicrobial compounds is to designmodulators, for example, inhibitors, of bacterial ribosome function. Bymodulating or inhibiting bacterial ribosome function, antimicrobialcompounds could interfere with essential processes such as RNAtranslation and protein synthesis, thereby providing an antimicrobialeffect. In fact, some antibiotic compounds such as erythromycin,clindamycin, and linezolid are known to bind to the ribosome.

SUMMARY

The present disclosure relates generally to the field of antimicrobialcompounds and to methods of making and using them. These compounds andtautomers thereof are useful for treating, preventing, reducing the riskof, or delaying the onset of microbial infections in humans and animals.The present disclosure also provides pharmaceutically acceptable saltsof these compounds and tautomers.

In some embodiments, provided herein is a compound of Formula (I):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein:

R₁ is selected from H, halo, and C₁₋₄ alkoxy;

R₂ is selected from H, halo, C₁₋₆ alkyl, C₁₋₄ haloalkyl, and OR^(a1);

R³ is selected H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, and C(O)OR^(a1);

W is selected from N and CR₄;

R₄ is selected from H, halo, OR^(a2), SR^(a2), 5-6 memberedheterocycloalkyl, S(O)₂R^(b2), C₁₋₆ alkyl, and C₂₋₆ alkenyl, wherein theC₁₋₆ alkyl is optionally substituted with a substituent selected fromOR^(a2);

R₅ is selected from H, halo, C₁₋₆ alkyl, and C₂₋₆ alkenyl, wherein theC₁₋₆ alkyl is optionally substituted with a substituent selected fromOR^(a2);

R₆ is selected from H, C₁₋₆ alkyl, C₃₋₅ cycloalkyl, and C₂₋₆ alkenyl,wherein the C₁₋₆ alkyl is optionally substituted with a substituentselected from OR^(a3), SR^(a3), and NR^(c3)R^(d3);

R_(7A) is selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, and C₂₋₆ alkenyl,wherein the C₁₋₆ alkyl is optionally substituted with a substituentselected from OR^(a3) and SR^(a3);

R_(7B) is H; or

R_(7A) and R_(7B) together with the carbon atom to which they areattached form a group selected from the group consisting of oxo, andC₃₋₆ cycloalkyl; or

R₆ and R_(7A) together with the carbon atoms to which they are attachedand the X atom connecting the two carbon atoms form a 5- to 6-memberedheterocycloalkyl containing 1-3 heteroatoms selected from N, O and S;

X is selected from O and NR₈;

R₈ is selected from H, C₁₋₆ alkyl, and C₁₋₄ haloalkyl, wherein the C₁₋₆alkyl is optionally substituted with R_(8A);

R_(8A) is selected from OR^(a3) and 5- to 6-membered heteroaryl, whereinthe 5- to 6-membered heteroaryl is optionally substituted with one ortwo C₁₋₆ alkyl;

R₉ is selected from H, C₂₋₄ alkenyl, C₁₋₄ haloalkyl and C₁₋₄ alkyloptionally substituted with a substituent selected from amino, C₁₋₄alkoxy, C₃₋₅ cycloalkyl, and 3- to 6-membered heterocycloalkyl;

R₁₀ is selected from H and C₂₋₆ alkenyl;

R_(A) is selected from H and C₁₋₆ alkyl;

L is selected from C₁₋₆ alkyl and C₂₋₆ alkenyl, wherein the C₁₋₆ alkylis optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, OR^(a4), SR^(a4), and Z;

R₁₁ is selected from H, C₁₋₆ alkyl, C₃₋₅ cycloalkyl, C₁₋₄ haloalkyl, andC₂₋₆ alkenyl, wherein the C₁₋₆ alkyl is optionally substituted with 1,2, or 3 substituents independently selected from CN, OR^(a5), SR^(a5),C(O)NR^(c5)R^(d5), NR^(c5)R^(d5), and S(O)₂R^(b5);

R₁₂ is selected from H and C₁₋₆ alkyl; or

R₁₁ and R₁₂ together with the carbon atom to which they are attachedform a C₃₋₅ cycloalkyl;

R₁₃ is selected from H, halo, and C₁₋₆ alkyl;

R₁₄ is selected from H, halo, and C₁₋₆ alkyl; and

R_(B) is selected H and C(═NR^(e5))R^(b5); or

R₁₁ and R_(B) together with the carbon atom to which R₁₁ is attached andthe nitrogen atom to which R_(B) is attached form a 5- to 6-memberedheterocycloalkyl containing 1-3 heteroatoms selected from N, O and S,wherein the 5- to 6-membered heterocycloalkyl is optionally substitutedwith oxo;

each R^(a1), R^(a2), R^(a3), R^(a4), R^(a5), R^(b2), R^(b5), R^(c3),R^(d3), R^(c5), and R^(d5) is independently selected from H, C₁₋₆ alkyl,C₁₋₄ haloalkyl, and 5-membered heteroaryl; and

R^(e5) is selected from H and C₁₋₄ alkyl; and Z is —O(CH₂CH₂O)CH₃.

In some embodiments, provided herein is a compound of Formula (II):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein:

R₁ is selected from H, halo, and C₁₋₄ alkoxy;

R₂ is selected from H, halo, C₁₋₆ alkyl, C₁₋₄ haloalkyl, and OR^(a1);

R³ is selected H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, and C(O)OR^(a1);

W is selected from N and CR₄;

R₄ is selected from H, halo, OR^(a2), SR^(a2), 5-6 memberedheterocycloalkyl, S(O)₂R^(b2), C₁₋₆ alkyl, and C₂₋₆ alkenyl, wherein theC₁₋₆ alkyl is optionally substituted with a substituent selected fromOR^(a2);

R₅ is selected from H, halo, C₁₋₆ alkyl, and C₂₋₆ alkenyl, wherein theC₁₋₆ alkyl is optionally substituted with a substituent selected fromOR^(a2);

R₆ is selected from H, C₁₋₆ alkyl, C₃₋₅ cycloalkyl, and C₂₋₆ alkenyl,wherein the C₁₋₆ alkyl is optionally substituted with a substituentselected from OR^(a3), SR^(a3), and NR^(c3)R^(d3);

R_(7A) is selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, and C₂₋₆ alkenyl,wherein the C₁₋₆ alkyl is optionally substituted with a substituentselected from OR^(a3) and SR^(a3);

R_(7B) is H; or

R_(7A) and R_(7B) together with the carbon atom to which they areattached form a group selected from the group consisting of oxo, andC₃₋₆ cycloalkyl; or

R₆ and R_(7A) together with the carbon atoms to which they are attachedand the X atom connecting the two carbon atoms form a 5- to 6-memberedheterocycloalkyl containing 1-3 heteroatoms selected from N, O and S;

X is selected from O and NR₈;

R₈ is selected from H, C₁₋₆ alkyl, and C₁₋₄ haloalkyl, wherein the C₁₋₆alkyl is optionally substituted with R_(8A);

R_(8A) is selected from OR^(a3) and 5- to 6-membered heteroaryl, whereinthe 5- to 6-membered heteroaryl is optionally substituted with one ortwo C₁₋₆ alkyl;

R₉ is selected from H, C₂₋₄ alkenyl, C₁₋₄ haloalkyl and C₁₋₄ alkyloptionally substituted with a substituent selected from amino, C₁₋₄alkoxy, C₃₋₅ cycloalkyl, and 3- to 6-membered heterocycloalkyl;

R₁₀ is selected from H and C₂₋₆ alkenyl;

R_(A) is selected from H and C₁₋₆ alkyl;

L is selected from C₁₋₆ alkyl and C₂₋₆ alkenyl, wherein the C₁₋₆ alkylis optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, OR^(a4), SR^(a4), and Z;

R₁₁ is selected from H, C₁₋₆ alkyl, C₃₋₅ cycloalkyl, C₁₋₄ haloalkyl, andC₂₋₆ alkenyl, wherein the C₁₋₆ alkyl is optionally substituted with 1,2, or 3 substituents independently selected from CN, OR^(a5), SR^(a5),C(O)NR^(c5)R^(d5), NR^(c5)R^(d5), and S(O)₂R^(b5);

R₁₂ is selected from H and C₁₋₆ alkyl; or

R₁₁ and R₁₂ together with the carbon atom to which they are attachedform a C₃₋₅ cycloalkyl;

R₁₃ is selected from H, halo, and C₁₋₆ alkyl;

R₁₄ is selected from H, halo, and C₁₋₆ alkyl; and

R_(B) is selected H and C(═NR^(e5))R^(b5); or

R₁₁ and R_(B) together with the carbon atom to which R₁₁ is attached andthe nitrogen atom to which R_(B) is attached form a 5- to 6-memberedheterocycloalkyl containing 1-3 heteroatoms selected from N, O and S,wherein the 5- to 6-membered heterocycloalkyl is optionally substitutedwith oxo;

each R^(a1), R^(a2), R^(a3), R^(a4), R^(a5), R^(b2), R^(b5), R^(c3),R^(d3), R^(c5), and R^(d5) is independently selected from H, C₁₋₆ alkyl,C₁₋₄ haloalkyl, and 5-membered heteroaryl; and

R^(e5) is selected from the group consisting of H and C₁₋₄ alkyl.

In some embodiments provided herein is a pharmaceutical compositioncomprising a compound of Formula I, or a tautomer thereof or apharmaceutically acceptable salt of the compound or tautomer, and apharmaceutically acceptable carrier.

In some embodiments provided herein is a method of treating a microbialinfection comprising administering to a subject in need thereof aneffective amount of a compound of Formula (I) or Formula (II), or atautomer thereof or a pharmaceutically acceptable salt of the compoundor tautomer, or a pharmaceutically acceptable composition as providedherein.

In some embodiments provided herein is a method of preventing amicrobial infection comprising administering to a subject in needthereof an effective amount of a compound of Formula (I) or Formula(II), or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, or a pharmaceutically acceptable composition asprovided herein.

In some embodiments provided herein is a method of reducing the risk ofa microbial infection comprising administering to a subject in needthereof an effective amount of a compound of Formula (I) or Formula(II), or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, or a pharmaceutically acceptable composition asprovided herein.

In some embodiments provided herein is a method of delaying the onset ofa microbial infection comprising administering to a subject in needthereof an effective amount of a compound of Formula (j) or Formula(II), or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, or a pharmaceutically acceptable composition asprovided herein.

In some embodiments provided herein is a method of treating a microbialinfection comprising administering to a subject in need thereof aneffective amount of a compound of Formula (I) or Formula (II), or atautomer thereof or a pharmaceutically acceptable salt of the compoundor tautomer, or a pharmaceutically acceptable composition as providedherein.

In some embodiments provided herein is a use of a compound of Formula(I) or Formula (H), or a tautomer thereof or a pharmaceuticallyacceptable salt of the compound or tautomer, in the manufacture of amedicament for treating, preventing, or reducing a microbial infectionin a subject.

In some embodiments provided herein is a compound of Formula (I) orFormula (II), or a tautomer thereof or a pharmaceutically acceptablesalt of the compound or tautomer, for use in treating, preventing, orreducing a microbial infection in a subject.

In addition, the disclosure provides methods of synthesizing theforegoing compounds and tautomers thereof, and pharmaceuticallyacceptable salts of said compounds and tautomers. Following synthesis,an effective amount of one or more of the compounds or tautomersthereof, or pharmaceutically acceptable salts of said compounds ortautomers can be formulated with a pharmaceutically acceptable carrierfor administration to a human or animal for use as antimicrobial agents,particularly as antibacterial agents. In certain embodiments, thecompounds of the present disclosure are useful for treating, preventing,reducing the risk of, or delaying the onset of microbial infections orfor the manufacture of a medicament for treating, preventing, reducingthe risk of, or delaying the onset of microbial infections.

Accordingly, the compounds or tautomers thereof, or pharmaceuticallyacceptable salts of said compounds or tautomers or their formulationscan be administered, for example, via oral, parenteral, intravenous,otic, ophthalmic, nasal, or topical routes, to provide an effectiveamount of the compound or tautomer thereof, or pharmaceuticallyacceptable salt of said compound or tautomer to the human or animal.

The foregoing and other aspects and embodiments of the disclosure can bemore fully understood by reference to the following detailed descriptionand claims.

DESCRIPTION OF THE DRAWINGS

FIG. 1 provides bar graphs illustrating the MIC distribution of RX-04A-Dfor all Enterobacteriaceae tested by species (n=68)

FIG. 2 provides a bar graph illustrating the MIC distributions of RX-04Afor CPE (n=36).

FIG. 3 provides a bar graph illustrating the MIC distributions of RX-04Afor MCR-1 isolates (N=14).

FIG. 4 provides a bar graph illustrating the MIC distributions ofRX-04A-D for A. baumannii isolates (n=10).

FIG. 5 provides bar graphs illustrating MIC distributions of RX-04A-Dfor P. aeruginosa (n=20).

DETAILED DESCRIPTION

The present disclosure utilizes a structure based drug design approachfor discovering and developing new antimicrobial agents. This approachstarts with a high resolution X-ray crystal of a ribosome to design newclasses of antimicrobial compounds having specific chemical structures,ribosome binding characteristics, and antimicrobial activity. Thisstructure based drug discovery approach is described in the followingpublication: Franceschi, F. and Duffy, E. M., “Structure-based drugdesign meets the ribosome”, Biochemical Pharmacology, vol. 71, pp.1016-1025 (2006).

Based on this structure based drug design approach, the presentdisclosure describes new chemical classes of antimicrobial compoundsuseful for treating bacterial infections in humans and animals. Withoutbeing limited by theories, these compounds are believed to inhibitbacterial ribosome function by binding to the ribosome. By takingadvantage of these ribosome binding sites, the antimicrobial compoundsof the present disclosure can provide better activity, especiallyagainst resistant strains of bacteria, than currently availableantibiotic compounds.

The present disclosure therefore fills an important ongoing need for newantimicrobial agents, particularly for antimicrobial agents, havingactivity against resistant pathogenic bacterial organisms.

The present disclosure provides a family of compounds or tautomersthereof, that can be used as antimicrobial agents, more particularly asantibacterial agents.

The present disclosure also includes pharmaceutically acceptable saltsof said compounds and tautomers.

The compounds or tautomers thereof, or pharmaceutically acceptable saltsof said compounds or tautomers disclosed herein can have asymmetriccenters. Compounds or tautomers thereof, or pharmaceutically acceptablesalts of said compounds or tautomers of the present disclosurecontaining an asymmetrically substituted atom can be isolated inoptically active or racemic forms. It is well known in the art how toprepare optically active forms, such as by resolution of racemic formsor by synthesis from optically active starting materials. Many geometricisomers of olefins, C═N double bonds, and the like can also be presentin the compounds or tautomers thereof, or pharmaceutically acceptablesalts of said compounds or tautomers disclosed herein, and all suchstable isomers are contemplated in the present disclosure. Cis and transgeometric isomers of the compounds or tautomers thereof, orpharmaceutically acceptable salts of said compounds or tautomers of thepresent disclosure are described and can be isolated as a mixture ofisomers or as separate isomeric forms. All chiral, diastercomeric,racemic, and geometric isomeric forms of a structure are intended,unless specific stereochemistry or isomeric form is specificallyindicated. All processes used to prepare compounds or tautomers thereof,or pharmaceutically acceptable salts of said compounds or tautomers ofthe present disclosure and intermediates made herein are considered tobe part of the present disclosure. All tautomers of shown or describedcompounds are also considered to be part of the present disclosure.Furthermore, the disclosure also includes metabolites of the compoundsdisclosed herein.

The disclosure also comprehends isotopically-labeled compounds ortautomers thereof, or pharmaceutically acceptable salts of saidcompounds or tautomers, which are identical to those recited in formulaeof the disclosure, but for the replacement of one or more atoms by anatom having an atomic mass or mass number different from the atomic massor mass number most commonly found in nature. Examples of isotopes thatcan be incorporated into compounds or tautomers thereof, orpharmaceutically acceptable salts of said compounds or tautomers of thedisclosure include isotopes of hydrogen, carbon, nitrogen, and fluorine,such as ³H, ¹¹C, ¹⁴C, and ¹⁸F.

The compounds of the present disclosure or tautomers thereof, orpharmaceutically acceptable salts of said compounds or tautomers thatcontain the aforementioned isotopes and/or isotopes of other atoms arewithin the scope of the present disclosure. Isotopically-labeledcompounds or tautomers thereof, or pharmaceutically acceptable salts ofsaid compounds or tautomers of the present disclosure, for example,those into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays Tritium, i.e., ³H and carbon-14, i.e., ¹⁴C, isotopes are areparticularly preferred due to their ease of preparation anddetectability. ¹¹C and ¹⁸F isotopes are particularly useful in PET(positron emission tomography). PET is useful in brain imaging. Further,substitution with heavier isotopes such as deuterium, i.e., ²H, canafford certain therapeutic advantages resulting from greater metabolicstability, i.e., increased in vivo half-life or reduced dosagerequirements and, hence, may be preferred in some circumstances.Isotopically labeled compounds or tautomers thereof, or pharmaceuticallyacceptable salts of said compounds or tautomers having a formula of thedisclosed herein can generally be prepared as described in theprocedures, Schemes and/or in the Examples disclosed herein, bysubstituting a non-isotopically labeled reagent with a readily availableisotopically labeled reagent. In one embodiment, the compounds ortautomers thereof, or pharmaceutically acceptable salts of saidcompounds or tautomers disclosed herein are not isotopically labeled.

When any variable (e.g., R) occurs more than one time in any constituentor formulae of the disclosed herein, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with one or more Rmoieties, then R at each occurrence is selected independently from thedefinition of R. Also, combinations of substituents and/or variables arepermissible, but only if such combinations result in stable compoundswithin a designated atom's normal valence.

A chemical structure showing a dotted line representation for a chemicalbond indicates that the bond is optionally present. For example, adotted line drawn next to a solid single bond indicates that the bondcan be either a single bond or a double bond.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent can be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent can be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible, but only if such combinations result in stable compounds.

In cases wherein compounds of the present disclosure, or tautomersthereof, or pharmaceutically acceptable salts of said compounds ortautomers thereof, contain nitrogen atoms, these, where appropriate, canbe converted to N-oxides by treatment with an oxidizing agent (e.g.,meta-chloroperoxybenzoic acid (mCPBA) and/or hydrogen peroxides). Thus,shown and claimed nitrogen atoms are considered to cover both the shownnitrogen and its N-oxide (N→O) derivative, as appropriate. In someembodiments, the present disclosure relates to N-oxides of the compoundsor tautomers thereof, or pharmaceutically acceptable salts of saidcompounds or tautomers disclosed herein.

One approach to developing improved anti-proliferative andanti-infective agents is to provide modulators (for example, inhibitors)of ribosome function.

Ribosomes are ribonucleoproteins, which are present in both prokaryotesand eukaryotes. Ribosomes are the cellular organelles responsible forprotein synthesis. During gene expression, ribosomes translate thegenetic information encoded in a messenger RNA into protein (Garrett etal. (2000) “The Ribosome: Structure, Function. Antibiotics and CellularInteractions.” American Society for Microbiology, Washington, D.C.).

Ribosomes comprise two nonequivalent ribonucleoprotein subunits. Thelarger subunit (also known as the “large ribosomal subunit”) is abouttwice the size of the smaller subunit (also known as the “smallribosomal subunit”). The small ribosomal subunit binds messenger RNA(mRNA) and mediates the interactions between mRNA and transfer RNA(tRNA) anticodons on which the fidelity of translation depends. Thelarge ribosomal subunit catalyzes peptide bond formation, i.e., thepeptidyl-transferase reaction of protein synthesis, and includes, atleast, three different tRNA binding sites known as the aminoacyl,peptidyl, and exit sites. The aminoacyl site or A-site accommodates theincoming aminoacyl-tRNA that is to contribute its amino acid to thegrowing peptide chain. Also, the A space of the A-site is important. Thepeptidyl site or P-site accommodates the peptidyl-tRNA complex, i.e.,the tRNA with its amino acid that is part of the growing peptide chain.The exit or E-site accommodates the deacylated tRNA after it has donatedits amino acid to the growing polypeptide chain.

1. Definitions

“Isomerism” means compounds that have identical molecular formulae butthat differ in the nature or the sequence of bonding of their atoms orin the arrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers”.Stereoisomers that are not mirror images of one another are termed“diastereoisomers”, and stereoisomers that are non-superimposable mirrorimages are termed “enantiomers”, or sometimes optical isomers. A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter”.

“Chiral isomer” means a compound with at least one chiral center. Acompound with one chiral center has two enantiomeric forms of oppositechirality and may exist either as an individual enantiomer or as amixture of enantiomers. A mixture containing equal amounts of individualenantiomeric forms of opposite chirality is termed a “racemic mixture”.A compound that has more than one chiral center has 2^(n-1) enantiomericpairs, where n is the number of chiral centers. Compounds with more thanone chiral center may exist as either an individual diastereomer or as amixture of diastereomers, termed a “diastereomeric mixture”. When onechiral center is present, a stereoisomer may be characterized by theabsolute configuration (R or S) of that chiral center. Absoluteconfiguration refers to the arrangement in space of the substituentsattached to the chiral center. The substituents attached to the chiralcenter under consideration are ranked in accordance with the SequenceRule of Cahn, Ingold and Prelog. (Cahn et al, Angew. Chem. Inter. Edit.1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahnand Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia1956, 12, 81; Cahn, J., Chem. Educ. 1964, 41, 116).

“Geometric Isomers” means the diastereomers that owe their existence tohindered rotation about double bonds. These configurations aredifferentiated in their names by the prefixes cis and trans, or Z and E,which indicate that the groups are on the same or opposite side of thedouble bond in the molecule according to the Cahn-Ingold-Prelog rules.

Further, the compounds discussed in this application include all atropicisomers thereof. “Atropic isomers” are a type of stereoisomer in whichthe atoms of two isomers are arranged differently in space. Atropicisomers owe their existence to a restricted rotation caused by hindranceof rotation of large groups about a central bond. Such atropic isomerstypically exist as a mixture, however, as a result of recent advances inchromatography techniques, it has been possible to separate mixtures oftwo atropic isomers in select cases.

Some compounds of the present disclosure can exist in a tautomeric formwhich is also intended to be encompassed within the scope of the presentdisclosure. “Tautomers” refers to compounds whose structures differmarkedly in the arrangement of atoms, but which exist in easy and rapidequilibrium. It is to be understood that compounds of present disclosuremay be depicted as different tautomers. It should also be understoodthat when compounds have tautomeric forms, all tautomeric forms areintended to be within the scope of the disclosure, and the naming of thecompounds does not exclude any tautomeric form.

The compounds and pharmaceutically acceptable salts of the presentdisclosure can exist in one or more tautomeric forms, including the enoland imine form and the keto and enamine form, and geometric isomers andmixtures thereof. All such tautomeric forms are included within thescope of the present disclosure. Tautomers exist as mixtures of atautomeric set in solution. In solid form, usually one tautomerpredominates. Even though one tautomer may be described, the presentdisclosure includes all tautomers of the compounds disclosed herein.

A tautomer is one of two or more structural isomers that exist inequilibrium and are readily converted from one isomeric form to another.This reaction results in the formal migration of a hydrogen atomaccompanied by a shift of adjacent conjugated double bonds. In solutionswhere tautomerization is possible, a chemical equilibrium of thetautomers can be reached. The exact ratio of the tautomers depends onseveral factors, including temperature, solvent, and pH. The concept oftautomers that are interconvertible by tautomerizations is calledtautomerism.

Of the various types of tautomerism that are possible, two are commonlyobserved. In keto-enol tautomerism, a simultaneous shift of electronsand a hydrogen atom occurs Ring-chain tautomerism, exhibited by glucoseand other sugars, arises as a result of the aldehyde group (—CHO) in asugar chain molecule reacting with one of the hydroxy groups (—OH) inthe same molecule to give it a cyclic (ring-shaped) form.

Tautomerizations are catalyzed by: Base: 1. deprotonation; 2. formationof a delocalized anion (e.g. an enolate); 3. protonation at a differentposition of the anion; Acid: 1. protonation, 2. formation of adelocalized cation, 3. deprotonation at a different position adjacent tothe cation.

Common tautomeric pairs include: ketone-enol, amide-nitrile,lactam-lactim, amide-imidic acid tautomerism in heterocyclic rings(e.g., in the nucleobases guanine, thymine, and cytosine), amine-enamineand enamine-enamine. Examples below are included for illustrativepurposes, and the present disclosure is not limited to the examples:

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom, usually a carbon, oxygen, or nitrogenatom, is replaced with a selection from the indicated group, providedthat the designated atom's normal valency is not exceeded, and that thesubstitution results in a stable compound. When a substituent is keto oroxo (i.e., ═O), then 2 hydrogens on the atom are replaced. Ring doublebonds, as used herein, are double bonds that are formed between twoadjacent ring atoms (e.g., C═C, C═N, N═N, etc.).

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. For example C₁₋₄ is intended toinclude C₁, C₂, C₃, and C₄. C₁₋₆alkyl is intended to include C₁, C₂, C₃,C₄, C₅, and C₆ alkyl groups and C₁₋₆ is intended to include C₁, C₂, C₃,C₄, C₅, C₆, C₇, and C₈. Some examples of alkyl include, but are notlimited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl,t-butyl, n-pentyl, s-pentyl, n-hexyl, n-heptyl, and n-octyl.

As used herein, “alkenyl” is intended to include hydrocarbon chains ofeither straight or branched configuration and one or more unsaturatedcarbon-carbon bonds that can occur in any stable point along the chain,such as ethenyl and propenyl. For example C₂₋₆ alkenyl is intended toinclude C₂, C₃, C₄, C₅, and C₆ alkenyl groups and C₂₋₈ alkenyl isintended to include C₂, C₃, C₄, C₅, C₆, C₇, and C₈.

As used herein, “alkylene” is intended to include moieties which arediradicals, i.e., having two points of attachment. A non-limitingexample of such alkylene moiety that is a diradical is —CH₂CH₂—, i.e., aC₂ alkyl group that is covalently bonded via each terminal carbon atomto the remainder of the molecule. The alkylene diradicals are also knownas “alkylenyl” radicals. Alkylene groups can be saturated or unsaturated(e.g., containing —CH═CH— or —C≡C— subunits), at one or severalpositions. In some embodiments, alkylene groups include 1 to 9 carbonatoms (for example, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2carbon atoms). Some examples of alkylene groups include, but not limitedto, methylene, ethylene, n-propylene, iso-propylene, n-butylene,iso-butylene, sec-butylene, tert-butylene, n-pentylene, iso-pentylene,sec-pentylene and neo-pentylene.

As used herein, “cycloalkyl” is intended to include saturated orunsaturated nonaromatic ring groups, such as cyclopropyl, cyclobutyl, orcyclopentyl. C₃₋₈ cycloalkyl is intended to include C₃, C₄, C₅, C₆, C₇,and C₈ cycloalkyl groups. Cycloalkyls may include multiple spiro- orfused rings.

As used herein, the term “heterocycloalkyl” refers to a saturated orunsaturated nonaromatic 3-8 membered monocyclic, 7-12 membered bicyclic(fused, bridged, or spiro rings), or 11-14 membered tricyclic ringsystem (fused, bridged, or spiro rings) having one or more heteroatoms(such as O, N, S, or Se), unless specified otherwise. A heterocycloalkylgroup containing a fused aromatic ring can be attached through anyring-forming atom including a ring-forming atom of the fused aromaticring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6membered heterocycloalkyl having 1 or 2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur and having one or moreoxidized ring members. In some embodiments, the heterocycloalkyl is amonocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or4 heteroatoms independently selected from nitrogen, oxygen, or sulfurand having one or more oxidized ring members. Examples ofheterocycloalkyl groups include, but are not limited to, piperidinyl,piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl,indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,triazolidinyl, tetrahyrofuranyl, oxiranyl, azetidinyl, oxetanyl,thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl,dihydropyranyl, pyranyl, morpholinyl, 1,4-diazepanyl, 1,4-oxazepanyl,2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl,2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl,1,4-dioxa-8-azaspiro[4.5]decanyl and the like.

As used herein, “amine” or “amino” refers to unsubstituted —NH₂ unlessotherwise specified.

As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo, andiodo substituents.

As used herein, “haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with one or more halogen(for example —C_(v)F_(w)H_(2v−w+1) wherein v=1 to 3 and w=1 to (2v+1)).Examples of haloalkyl include, but are not limited to, trifluoromethyl,trichloromethyl, pentafluoroethyl, and pentachloroethyl.

The term “haloalkoxy” as used herein refers to an alkoxy group, asdefined herein, which is substituted one or more halogen. Examples ofhaloalkoxy groups include, but are not limited to, trifluoromethoxy,difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

As used herein, “alkoxyl” or “alkoxy” refers to an alkyl group asdefined above with the indicated number of carbon atoms attached throughan oxygen bridge. C₁₋₆ alkoxy, is intended to include C₁, C₂, C₃, C₄,C₅, and C₆ alkoxy groups. C₁₋₈ alkoxy, is intended to include C₁, C₂,C₃, C₄, C₅, C₆, C₇, and C₈ alkoxy groups.

Examples of alkoxy include, but are not limited to, methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy,s-pentoxy, n-heptoxy, and n-octoxy.

As used herein, “Aryl” includes groups with aromaticity, including“conjugated,” or multicyclic systems with at least one aromatic ring anddo not contain any heteroatom in the ring structure. Aryl may bemonocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term“C_(n-m) aryl” refers to an aryl group having from n to m ring carbonatoms. In some embodiments, aryl groups have from 6 to 10 carbon atoms.In some embodiments, the aryl group is phenyl or naphtyl.

As used herein, the term “aromatic heterocycle”, “aromatic heterocyclic”or “heteroaryl” ring is intended to mean a stable 5, 6, 7, 8, 9, 10, 11,or 12-membered monocyclic or bicyclic aromatic ring which consists ofcarbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4or 1-5 or 1-6 heteroatoms, independently selected from nitrogen, oxygen,and sulfur. In the case of bicyclic aromatic heterocyclic or heterocycleor heteroaryl rings, only one of the two rings needs to be aromatic(e.g., 2,3-dihydroindole), though both can be (e.g., quinoline). Thesecond ring can also be fused or bridged as defined above forheterocycles. The nitrogen atom can be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, as defined). Thenitrogen and sulfur heteroatoms can optionally be oxidized (i.e., N→Oand S(O)_(p), wherein p=1 or 2). In certain compounds, the total numberof S and O atoms in the aromatic heterocycle is not more than 1.

Examples of aromatic heterocycles, aromatic heterocyclics or heteroarylsinclude, but are not limited to, acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, benzooxadiazoly,carbazolyl, 4aH-carbazolyl, carbolinyl, cinnolinyl, furazanyl,imidazolyl, imidazolonyl, 1H-indazolyl, indolizinyl, indolyl,3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl,isoquinolinyl, isothiazolyl, isoxazolyl, methylbenztriazolyl,methylfuranyl, methylimidazolyl, methylthiazolyl, naphthyridinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridooxazolyl,pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyridinonyl, pyridyl,pyrimidinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, tetrahydroquinolinyl, tetrazolyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, triazolopyrimidinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,5-triazolyl, and 1,3,4-triazolyl.

The term “hydroxyalkyl” means an alkyl group as defined above, where thealkyl group is substituted with one or more OH groups. Examples ofhydroxyalkyl groups include HO—CH₂—, HO—CH₂—CH₂— and CH₃—CH(OH)—.

The term “cyano” as used herein means a substituent having a carbon atomjoined to a nitrogen atom by a triple bond, i.e., C≡N.

As used herein, “oxo” is means a “═O” group.

As used herein, the phrase “pharmaceutically acceptable” refers to thosecompounds or tautomers thereof, or salts thereof, materials,compositions, and/or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of humanbeings and animals without excessive toxicity, irritation, allergicresponse, or other problem or complication, commensurate with areasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds or tautomers thereof, wherein the parentcompound or a tautomer thereof, is modified by making of the acid orbase salts thereof of the parent compound or a tautomer thereof.Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like.

The pharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound, or atautomer thereof, formed, for example, from non-toxic inorganic ororganic acids. For example, such conventional non-toxic salts include,but are not limited to, those derived from inorganic and organic acidsselected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic,ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric,edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic,gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic,hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic,hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic,maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic,pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic,propionic, salicylic, stearic, subacetic, succinic, sulfamic,sulfanilic, sulfuric, tannic, tartaric, and toluene sulfonic.

The pharmaceutically acceptable salts of the present disclosure can besynthesized from the parent compound or a tautomer thereof that containsa basic or acidic moiety by conventional chemical methods. Generally,such pharmaceutically acceptable salts can be prepared by reacting thefree acid or base forms of these compounds or tautomers thereof with astoichiometric amount of the appropriate base or acid in water or in anorganic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa.,USA, p. 1445 (1990).

As used herein, “stable compound” and “stable structure” are meant toindicate a compound that is sufficiently robust to survive isolation toa useful degree of purity from a reaction mixture, and formulation intoan efficacious therapeutic agent.

As used herein, the term “treating” means to provide a therapeuticintervention to cure or ameliorate an infection. In some embodiments,“treating” refers to administering a compound or pharmaceuticalcomposition as provided herein for therapeutic purposes. The term“therapeutic treatment” refers to administering treatment to a patientalready suffering from a disease thus causing a therapeuticallybeneficial effect, such as ameliorating existing symptoms, amelioratingthe underlying metabolic causes of symptoms, postponing or preventingthe further development of a disorder, and/or reducing the severity ofsymptoms that will or are expected to develop.

As used herein, the term “preventing”, as used herein means, tocompletely or almost completely stop an infection from occurring, forexample when the patient or subject is predisposed to an infection or atrisk of contracting an infection. Preventing can also includeinhibiting, i.e., arresting the development, of an infection.

As used herein, the term “reducing the risk of”, as used herein, meansto lower the likelihood or probability of an infection occurring, forexample when the patient or subject is predisposed to an infection or atrisk of contracting an infection.

As used herein, “unsaturated” refers to compounds having at least onedegree of unsaturation (e.g., at least one multiple bond) and includespartially and fully unsaturated compounds.

As used herein, the term “effective amount” refers to an amount of acompound or a tautomer thereof, or a pharmaceutically acceptable salt ofsaid compound or tautomer (including combinations of compounds and/ortautomers thereof, and/or pharmaceutically acceptable salts of saidcompound or tautomer) of the present disclosure that is effective whenadministered alone or in combination as an antimicrobial agent. Forexample, an effective amount refers to an amount of the compound ortautomer thereof, or a pharmaceutically acceptable salt said compound ortautomer that is present in a composition, a formulation or on a medicaldevice given to a recipient patient or subject sufficient to elicitbiological activity, for example, anti-infective activity, such as e.g.,anti-microbial activity, anti-bacterial activity, anti-fungal activity,anti-viral activity, or anti-parasitic activity.

The term “prophylactically effective amount” means an amount of acompound or a tautomer of said compound or tautomer, or apharmaceutically acceptable salt of said compound or tautomer (includingcombinations of compounds and/or tautomers thereof, and/orpharmaceutically acceptable salts thereof), of the present disclosurethat is effective prophylactically when administered alone or incombination as an antimicrobial agent. For example, a prophylacticallyeffective amount refers to an amount of the compound or tautomerthereof, or a pharmaceutically acceptable salt of said compound ortautomer that is present in a composition, a formulation, or on amedical device given to a recipient patient or subject sufficient toprevent or reduce the risk of an infection due to a surgical procedureor an invasive medical procedure.

In the specification, the singular forms also include the plural, unlessthe context clearly dictates otherwise. Unless defined otherwise, alltechnical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisdisclosure belongs. In the case of conflict, the present specificationwill control. As used herein, “mammal” refers to human and non-humanpatients.

As used herein, the term ESBL is extended spectrum beta-lactamase. Theterm KPC is Klebsiella pneumoniae carbapenemase.

As used herein, the term acute bacterial skin and skin structureinfection (ABSSSI) encompasses complicated skin and skin structureinfections (cSSSI) and complication skin and soft tissue infections(cSSTI), which have been used interchangeably. The terms uncomplicatedskin and skin structure infections (uCSSSI) and uncomplicated skin andsoft tissue infections (uCSSTI) have been used interchangeably.

As used herein, the term “spp.” is the abbreviation for species.

As used herein, the term “formulae of the disclosure” or “formulaedisclosed herein” includes one or more of the Formulae: (I), (Ia),(Ia-1), (Ia-2), (Ib-a), (Ib), (Ia-3), (Ic), (Ic-1), (Id), (Ie), (If),(Ig), (Ie-1), (Ih), (Ii), (Ij), and (Ik).

As used herein, the term “compound of the disclosure” or “compounddisclosed herein” includes one or more compounds of the formulae of thedisclosure or a compound explicitly disclosed herein.

All percentages and ratios used herein, unless otherwise indicated, areby weight.

Throughout the description, where compositions are described as having,including, or comprising specific components, or where processes aredescribed as having, including, or comprising specific process steps, itis contemplated that compositions of the present disclosure also consistessentially of, or consist of, the recited components, and that theprocesses of the present disclosure also consist essentially of, orconsist of, the recited processing steps. Further, it should beunderstood that the order of steps or order for performing certainactions are immaterial so long as the invention remains operable.Moreover, two or more steps or actions can be conducted simultaneously.

2. Compounds of the Disclosure

In some embodiments, provided herein is a compound of Formula (I):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein:

R₁ is selected from H, halo, and C₁₋₄ alkoxy;

R₂ is selected from H, halo, C₁₋₆ alkyl, C₁₋₄ haloalkyl, and OR^(a1);

R³ is selected H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, and C(O)OR^(a1);

W is selected from N and CR₄;

R₄ is selected from H, halo, OR^(a2), SR^(a2), 5-6 memberedheterocycloalkyl, S(O)₂R^(b2), C₁₋₆ alkyl, and C₂₋₆ alkenyl, wherein theC₁₋₆ alkyl is optionally substituted with a substituent selected fromOR^(a2);

R₅ is selected from H, halo, C₁₋₆ alkyl, and C₂₋₆ alkenyl, wherein theC₁₋₆ alkyl is optionally substituted with a substituent selected fromOR^(a2);

R₆ is selected from H, C₁₋₆ alkyl, C₃₋₅ cycloalkyl, and C₂₋₆ alkenyl,wherein the C₁₋₆ alkyl is optionally substituted with a substituentselected from OR^(a3), SR^(a3), and NR^(c3)R^(d3);

R_(7A) is selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, and C₂₋₆ alkenyl,wherein the C₁₋₆ alkyl is optionally substituted with a substituentselected from OR^(a3) and SR^(a3);

R_(7B) is H; or

R_(7A) and R_(7B) together with the carbon atom to which they areattached form a group selected from the group consisting of oxo, andC₃₋₆ cycloalkyl; or

R₆ and R_(7A) together with the carbon atoms to which they are attachedand the X atom connecting the two carbon atoms form a 5- to 6-memberedheterocycloalkyl containing 1-3 heteroatoms selected from N, O and S;

X is selected from O and NR₈;

R₈ is selected from H, C₁₋₆ alkyl, and C₁₋₄ haloalkyl, wherein the C₁₋₆alkyl is optionally substituted with R_(8A);

R_(8A) is selected from OR^(a3) and 5- to 6-membered heteroaryl, whereinthe 5- to 6-membered heteroaryl is optionally substituted with one ortwo C₁₋₆ alkyl;

R₉ is selected from H, C₂₋₄ alkenyl, C₁₋₄ haloalkyl and C₁₋₄ alkyloptionally substituted with a substituent selected from amino, C₁₋₄alkoxy, C₃₋₅ cycloalkyl, and 3- to 6-membered heterocycloalkyl;

R₁₀ is selected from H and C₂₋₆ alkenyl;

R_(A) is selected from H and C₁₋₆ alkyl;

L is selected from C₁₋₆ alkyl and C₂₋₆ alkenyl, wherein the C₁₋₆ alkylis optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, OR^(a4), SR^(a4), and Z;

R₁₁ is selected from H, C₁₋₆ alkyl, C₃₋₅ cycloalkyl, C₁₋₄ haloalkyl, andC₂₋₆ alkenyl, wherein the C₁₋₆ alkyl is optionally substituted with 1,2, or 3 substituents independently selected from CN, OR^(a5), SR^(a5),C(O)NR^(c5)R^(d5), NR^(c5)R^(d5), and S(O)₂R^(b5);

R₁₂ is selected from H and C₁₋₆ alkyl; or

R₁₁ and R₁₂ together with the carbon atom to which they are attachedform a C₃₋₅ cycloalkyl;

R₁₃ is selected from H, halo, and C₁₋₆ alkyl;

R₁₄ is selected from H, halo, and C₁₋₆ alkyl; and

R_(B) is selected H and C(═NR^(e5))R^(b5); or

R₁₁ and R_(B) together with the carbon atom to which R₁₁ is attached andthe nitrogen atom to which R_(B) is attached form a 5- to 6-memberedheterocycloalkyl containing 1-3 heteroatoms selected from N, O and S,wherein the 5- to 6-membered heterocycloalkyl is optionally substitutedwith oxo;

each R^(a1), R^(a2), R^(a3), R^(a4), R^(a5), R^(b2), R^(b5), R^(c3),R^(d3), R^(c5), and R^(d5) is independently selected from H, C₁₋₆ alkyl,C₁₋₄ haloalkyl, and 5-membered heteroaryl; and

R^(e5) is selected from H and C₁₋₄ alkyl; and Z is —O(CH₂CH₂O)CH₃.

In some embodiments, the present application provides a compound ofFormula (II):

or tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein:

R₁ is selected from H, halo;

R₂ is selected from H, halo, C₁₋₆ alkyl, C₁₋₄ haloalkyl, and OR^(a1);

R³ is selected H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, and C(O)OR^(a1);

W is selected from N and CR₄;

R₄ is selected from H, halo, C₁₋₆ alkyl, OR^(a2), SR^(a2), 5-6 memberedheterocycloalkyl, and S(O)₂R^(b2);

R₅ is selected from H, halo;

R₆ is selected from H, C₁₋₆ alkyl, C₃₋₅ cycloalkyl, and C₂₋₆ alkenyl,wherein the C₁₋₆ alkyl is optionally substituted with a substituentselected from OR^(a3), SR^(a3), and NR^(c3)R^(d3);

R_(7A) is selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, and C₂₋₆ alkenyl,wherein the C₁₋₆ alkyl is optionally substituted with a substituentselected from OR^(a3) and SR^(a3);

R_(7B) is H; or

R_(7A) and R_(7B) together with the carbon atom to which they areattached form a group selected from the group consisting of oxo, andC₃₋₆ cycloalkyl; or

R₆ and R_(7A) together with the carbon atoms to which they are attachedand the X atom connecting the two carbon atoms form a 5- to 6-memberedheterocycloalkyl containing 1-3 heteroatoms independently selected fromN, O and S, wherein the 5- to 6-membered heterocycloalkyl is optionallysubstituted with a substituent selected from C(═NR^(e3))R^(b3), andNR^(e3)R^(d3);

X is selected from O and NR₈;

R₈ is selected from H, C₁₋₆ alkyl, and C₁₋₄ haloalkyl, wherein the C₁₋₆alkyl is optionally substituted with R_(8A);

R_(8A) is selected from 5- to 6-membered heteroaryl, and OR^(a3),wherein the 5- to 6-membered heteroaryl is optionally substituted with1, or 2 C₁₋₆ alkyl;

R₉ is selected from H, C₂₋₄ alkenyl, C₁₋₄ haloalkyl and C₁₋₄ alkyloptionally substituted with a substituent selected from amino, C₁₋₄alkoxy, C₃₋₅ cycloalkyl, and 3- to 6-membered heterocycloalkyl;

R₁₀ is selected from H and C₂₋₆ alkenyl;

R_(A) is selected from H and C₁₋₆ alkyl;

L is selected from C₁₋₆ alkyl and C₂₋₆ alkenyl, wherein the C₁₋₆ alkylis optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, OR^(a4), SR^(a4), and Z;

R₁₁ is selected from H, C₁₋₆ alkyl, C₃₋₅ cycloalkyl, C₁₋₄ haloalkyl, andC₂₋₆ alkenyl, wherein the C₁₋₆ alkyl is optionally substituted with 1,2, or 3 substituents independently selected from CN, OR^(a5), SR^(a5),C(O)NR^(c5)R^(d5), NR^(c5)R^(d5), and S(O)₂R^(b5);

R₁₂ is selected from H and C₁₋₆ alkyl; or

R₁₁ and R₁₂ together with the carbon atom to which they are attachedform a C₃₋₅ cycloalkyl;

R₁₃ is selected from H, halo, and C₁₋₆ alkyl;

R₁₄ is selected from H, halo, and C₁₋₆ alkyl; and

R_(B) is selected H and C(═NR^(e5))R^(b5); or

R₁₁ and R_(B) together with the carbon atom to which R₁₁ is attached andthe nitrogen atom to which R_(B) is attached form a 5- to 6-memberedheterocycloalkyl containing 1-3 heteroatoms selected from N, O and S,wherein the 5- to 6-membered heterocycloalkyl is optionally substitutedwith oxo;

each R^(a1), R^(a2), R^(a3), R^(a4), R^(a5), R^(b2), R^(b5), R^(c3),R^(d3), R^(c5), and R^(d5) is independently selected from H, C₁₋₆ alkyl,C₁₋₄ haloalkyl, and 5-membered heteroaryl; and

each R^(e3) and R^(e5) is independently selected from H and C₁₋₄ alkyl.

In some embodiments of Formula (I) or Formula (II), R₁ is halo. In someembodiments, R₁ is selected from H and fluoro. In some embodiments, R₁is fluoro. In some embodiments, R₁ is H.

In some embodiments of Formula (I), R₁ is C₁₋₄ alkoxy. For example, R₁can be methoxy.

In some embodiments of Formula (I) or Formula (II), R₂ is selected fromH, halo, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy. In some embodiments, R₂ ishalo. In some embodiments, R₂ is C₁₋₄ haloalkyl in some embodiments, R₂is C₁₋₄ haloalkoxy. In some embodiments, R₂ is selected from halo, C₁₋₄haloalkyl, and C₁₋₄ haloalkoxy. In some embodiments, R₂ is selected fromH, trifluoromethoxy, trifluoromethyl and chloro. In some embodiments, R₂is selected from trifluoromethoxy, trifluoromethyl and chloro. In someembodiments, R₂ is trifluoromethoxy. In some embodiments, R₂ istrifluoromethyl. In some embodiments, R₂ is chloro. In some embodiments,R₂ is H.

In some embodiments of Formula (I) or Formula (II), R₁ is halo and R₂ ishalo. In some embodiments, R₁ is fluoro and R₂ is chloro. In someembodiments, R₁ is fluoro and R₂ is trifluoromethoxy. In someembodiments, R₁ is fluoro and R₂ is trifluoromethyl. In someembodiments, R₁ is H and R₂ is trifluoromethyl.

In some embodiments of Formula (I) or Formula (II), R₁ is H, R₂ is H,and R₃ is not H.

In some embodiments of Formula (I) or Formula (II), R₃ is selected fromH, C₁₋₄ haloalkyl, and C(O)OR^(a1). In some embodiments, R₃ is selectedfrom H, C₁₋₄ haloalkyl, and C(O)C₁₋₄ alkoxy. In some embodiments, R₃ isselected from H, trifluoromethyl, and C(═O)(methoxy). In someembodiments, R₃ is trifluoromethyl. In some embodiments, R₃ isC(═O)(methoxy). In some embodiments, R₃ is H.

In some embodiments of Formula (I) or Formula (I), R₁ is H, R₂ is H, andR₃ is trifluoromethyl. In some embodiments, R₁ is H, R₂ is H, and R₃ isC(═O)(methoxy).

In some embodiments of Formula (I) or Formula (II), W is N.

In some embodiments of Formula (I) or Formula (TI), W is CR₄.

In some embodiments of Formula (I) or Formula (II), R₄ is selected fromH, halo, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, S(C₁₋₄ alkyl),6-membered heterocycloalkyl, and S(O)₂ C₁₋₄ alkyl. In some embodiments,R₄ is selected from halo, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,S(C₁₋₄ alkyl), 6-membered heterocycloalkyl, and S(O)₂ C₁₋₄ alkyl. Insome embodiments, R₄ is halo. In some embodiments, R₄ is C₁₋₄ alkoxy. Insome embodiments, R₄ is C₁₋₄ haloalkoxy. In some embodiments, R₄ isS(C₁₋₄ alkyl). In some embodiments, R₄ is 6-membered heterocycloalkyl.In some embodiments, R₄ is S(O)₂ C₁₋₄ alkyl. In some embodiments, R₄ isselected from H, fluoro, chloro, methylthio, methoxy, methyl,S(═O)₂(methyl), trifluoromethoxy, and N-morpholino. In some embodiments,R₄ is selected from fluoro, chloro, methylthio, methoxy, methyl,S(═O)₂(methyl), trifluoromethoxy, and N-morpholino. In some embodiments,R₄ is fluoro. In some embodiments, R₄ is chloro. In some embodiments, R₄is methylthio. In some embodiments, R₄ is methoxy. In some embodiments,R₄ is methyl. In some embodiments, R₄ is S(═O)₂(methyl). In someembodiments, R₄ is trifluoromethoxy. In some embodiments, R₄ isN-morpholino. In some embodiments, R₄ is H. In some embodiments, R₄ isnot H.

In some embodiments of Formula (I) or Formula (II), R₅ is halo. In someembodiments, R₅ is selected from H and F. In some embodiments, R₅ is F.In some embodiments, R₅ is H.

In some embodiments of Formula (I) or Formula (II), R₅ is halo and R₄ isselected from halo, S(C₁₋₄ alkyl), and 6-membered heterocycloalkyl. Insome embodiments, R₅ is halo, and R₄ is S(C₁₋₄ alkyl). In someembodiments, R₅ is fluoro and R₄ is selected from fluoro, methylthio,and N-morpholino. In some embodiments, R₅ is fluoro and R₄ ismethylthio. In some embodiments, R₅ is fluoro and R₄ is fluoro. In someembodiments, R₅ is fluoro and R₄ is 6-membered heterocycloalkyl. In someembodiments, R₅ is halo and R₄ is N-morpholino. In some embodiments, R₅is fluoro and R₄ is N-morpholino. In some embodiments of Formula (I) orFormula (II), R₆ is selected from H, C₃₋₅ cycloalkyl, C₂₋₆ alkenyl, andC₁₋₆ alkyl optionally substituted with a substituent selected fromhydroxyl, C₁₋₄ alkoxy, S(C₁₋₄ alkyl), amino, and NH(5-memberedheteroaryl). In some embodiments, R₆ is selected from C₃₋₅ cycloalkyl,C₂₋₆ alkenyl, and C₁₋₆ alkyl optionally substituted with a substituentselected from hydroxyl, C₁₋₄ alkoxy, S(C₁₋₄ alkyl), amino, andNH(5-membered heteroaryl). In some embodiments, R₆ is C₃₋₅ cycloalkyl.In some embodiments, R₆ is C₂₋₆ alkenyl. In some embodiments, R₆ is C₁₋₆alkyl optionally substituted with a substituent selected from hydroxyl,C₁₋₄ alkoxy, S(C₁₋₄ alkyl), amino, and NH(5-membered heteroaryl). Insome embodiments, R₆ is selected from H, cyclopropyl, ethenyl,aminomethyl, hydroxymethyl, CH₂NH-imidazolyl, methylthiomethyl, andmethoxymethyl. In some embodiments, R₆ is cyclopropyl. In someembodiments, R₆ is ethenyl. In some embodiments, R₆ is aminomethyl. Insome embodiments, R₆ is hydroxymethyl. In some embodiments, R₆ isCH₂NH-imidazole. In some embodiments, R₆ is methylthiomethyl. In someembodiments, R₆ is methoxymethyl. In some embodiments, R₆ is selectedfrom cyclopropyl, ethenyl, aminomethyl, hydroxymethyl, CH₂NH-imidazolyl,methylthiomethyl, and methoxymethyl. In some embodiments, R₆ is H.

In some embodiments of Formula (I) or Formula (H), R_(7A) is selectedfrom H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, and C₂₋₆ alkenyl.In some embodiments, R_(7A) is selected from C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, and C₂₋₆ alkenyl. In some embodiments, R_(7A) is C₁₋₆alkyl. In some embodiments, R_(7A) is C₁₋₄ haloalkyl. In someembodiments, R_(7A) is C₁₋₄ hydroxyalkyl. In some embodiments, R_(7A) isC₂₋₆ alkenyl. In some embodiments, R_(7A) is selected from H, methyl,trifluoromethyl, hydroxymethyl, difluoromethyl, and ethenyl. In someembodiments, R_(7A) is selected from methyl, trifluoromethyl,hydroxymethyl, difluoromethyl, and ethenyl. In some embodiments, R_(7A)is methyl. In some embodiments, R_(7A) is trifluoromethyl. In someembodiments, R_(7A) is hydroxymethyl. In some embodiments, R_(7A)difluoromethyl. In some embodiments, R_(7A) is ethenyl. In someembodiments, R_(7A) is H.

In some embodiments of Formula (I) or Formula (II), R_(7A) and R_(7B)together with the carbon atom to which they are attached form oxo. Insome embodiments, R_(7A) and R_(7B) together with the carbon atom towhich they are attached form C₃₋₆ cyclopropyl.

In some embodiments of Formula (I) or Formula (II), R₆ is selected fromC₂₋₆ alkenyl, C₁₋₆ hydroxyalkyl, and C₁₋₆ alkylene-NH(5-memberedheteroaryl), and R_(7A) is C₁₋₆ alkyl. In some embodiments, R₆ isselected from ethenyl, hydroxymethyl, and CH₂NH-imidazole, and R_(7A) isC₁₋₆ alkyl. In some embodiments, R₆ is selected from ethenyl and R_(7A)is methyl. In some embodiments, R₆ is hydroxymethyl, and R_(7A) ismethyl. In some embodiments, R₆ is CH₂NH-imidazole, and R_(7A) ismethyl. In some embodiments, R₆ is H and R_(7A) is C₁₋₆ alkyl. In someembodiments, R₆ is H and R_(7A) is methyl.

In some embodiments of Formula (I) or Formula (II), the carbon atom towhich R₆ is attached is in (S) configuration according toCahn-Ingold-Prelog nomenclature. In some embodiments, the carbon atom towhich R₆ is attached is in (R) configuration according toCahn-Ingold-Prelog nomenclature. In some embodiments, thestereochemistry at the carbon atom bound to R₆ is as shown below:

wherein x indicates a point of attachment to the X atom.

In some embodiments, the stereochemistry at the carbon atom bound to R₆is as shown below:

wherein x indicates a point of attachment to the X atom.

In some embodiments of Formula (I) or Formula (II), the carbon atom towhich R_(7A) is attached is in (S) configuration according toCahn-Ingold-Prelog nomenclature. In some embodiments, the carbon atom towhich R_(7A) is attached is in (R) configuration according toCahn-Ingold-Prelog nomenclature.

In some embodiments, the stereochemistry at the carbon atom bound toR_(7A) is as shown below:

wherein x indicates a point of attachment to the X atom.

In some embodiments, the stereochemistry at the carbon atom bound toR_(7A) is as shown below:

wherein x indicates a point of attachment to the X atom.

In some embodiments of Formula (I) or Formula (II), R₆ and R_(7A)together with the carbon atoms to which they are attached and the X atomconnecting the two carbon atoms form a 6-membered heterocycloalkylcontaining 1-3 heteroatoms selected from N, O and S, wherein the6-membered heterocycloalkyl is optionally substituted with a substituentselected from C(═NH)C₁₋₆ alkyl, and di(C₁₋₆ alkyl)amino.

In some embodiments of Formula (I) or Formula (II), R₆ and R_(7A)together with the carbon atoms to which they are attached and the X atomconnecting the two carbon atoms form a ring of any one of the followingformulae:

wherein any one of the formulae is optionally substituted withC(═NH)C₁₋₆ alkyl, or di(C₁₋₆ alkyl)amino.

In some embodiments of Formula (I) or Formula (II), R₆ and R_(7A)together with the carbon atoms to which they are attached and the X atomconnecting the two carbon atoms form a ring of the following formulae:

wherein x indicates a point of attachment to the ring containing the Watom and substituted with R₅.

In some embodiments of Formula (I) or Formula (II), R₆ and R_(7A)together with the carbon atoms to which they are attached and the X atomconnecting the two carbon atoms form a ring of any one of the followingformulae:

wherein any one of the formulae is optionally substituted withC(═NH)methyl, or dimethylamino.

In some embodiments of Formula (I) or Formula (I), R₆ and R_(7A)together with the carbon atoms to which they are attached and the X atomconnecting the two carbon atoms form a ring of any one of the followingformulae:

wherein any one of the formulae is optionally substituted withC(═NH)methyl, or dimethylamino.

In some embodiments of Formula (I) or Formula (II), R₆ and R_(7A)together with the carbon atoms to which they are attached and the X atomconnecting the two carbon atoms form a ring of formula:

In some embodiments of Formula (I) or Formula (II), R₆ and R_(7A)together with the carbon atoms to which they are attached and the X atomconnecting the two carbon atoms form a ring of formula:

wherein x indicates a point of attachment to the ring containing the Watom and substituted with R₅.

In some embodiments of Formula (I) or Formula (TI), R₆ and R_(7A)together with the carbon atoms to which they are attached and the X atomconnecting the two carbon atoms form a ring of formula:

In some embodiments of Formula (I) or Formula (II), R₆ and R_(7A)together with the carbon atoms to which they are attached and the X atomconnecting the two carbon atoms form a ring of formula:

wherein x indicates a point of attachment to the ring containing the Watom and substituted with R₅.

In some embodiments of Formula (I) or Formula (II), R₆ and R_(7A)together with the carbon atoms to which they are attached and the X atomconnecting the two carbon atoms form a ring of any one of the followingformulae:

wherein x indicates a point of attachment to the ring containing the Watom and substituted with R₅.

In some embodiments of Formula (I) or Formula (II), R₆ and R_(7A)together with the carbon atoms to which they are attached and the X atomconnecting the two carbon atoms form a ring of any one of the followingformulae:

wherein x indicates a point of attachment to the ring containing the Watom and substituted with R₅.

In some embodiments of Formula (I) or Formula (II), R₆ and R_(7A)together with the carbon atoms to which they are attached and the X atomconnecting the two carbon atoms form a ring of any one of the followingformulae:

wherein x indicates a point of attachment to the ring containing the Watom and substituted with R₅.

In some embodiments of Formula (I) or Formula (II), X is O. In someembodiments of Formula (I) or Formula (II), X is NR₈.

In some embodiments of Formula (I) or Formula (II), R₈ is selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₆ alkyl substitutedwith C₁₋₆ alkoxy, and C₁₋₆ alkyl substituted with 5- to 6-memberedheteroaryl, wherein the 5- to 6-membered heteroaryl is optionallysubstituted with one or two C₁₋₆ alkyl. In some embodiments, R₈ is C₁₋₆alkyl. In some embodiments, R₈ is C₁₋₄ haloalkyl. In some embodiments,R₈ is C₁₋₄ hydroxyalkyl. In some embodiments, R₈ is C₁₋₆ alkylsubstituted with C₁₋₆ alkoxy. In some embodiments, R₈ is C₁₋₆ alkylsubstituted with 5- to 6-membered heteroaryl, wherein the 5- to6-membered heteroaryl is optionally substituted with 1, or 2 C₁₋₆ alkyl.

In some embodiments of Formula (I), R₈ is selected from H, methyl,tert-butyl, 2-fluoroethenyl, 3-fluoropropyl, 2-methoxyethyl,3-hydroxypropyl, 2-methyl-3-hydroxy-propyl, 2-(pyridinyl)ethyl,2-(imidazolyl)ethyl, (imidazolyl)methyl, and (oxazolyl)methyl, whereineach pyridinyl, imidazolyl, and oxazolyl is optionally substituted with1 or 2 methyl.

In some embodiments of Formula (I) or Formula (II), R₈ is selected fromH, methyl, 3-fluoropropyl, 2-methoxyethyl, 3-hydroxypropyl,2-(pyridinyl)ethyl, 2-(imidazolyl)ethyl, (imidazolyl)methyl, and(oxazolyl)methyl, wherein each pyridinyl, imidazolyl, and oxazolyl isoptionally substituted with 1 or 2 methyl.

In some embodiments of Formula (I) or Formula (II), R₈ is selected fromany one of the following formulae:

In some embodiments of Formula (I) or Formula (II), R₈ is selected frommethyl, 3-fluoropropyl, 2-methoxyethyl, and 3-hydroxypropyl. In someembodiments, R₈ is methyl. In some embodiments, R₈ is 3-fluoropropyl. Insome embodiments, R₈ is 2-methoxyethyl. In some embodiments, R₈ is3-hydroxypropyl. In some embodiments, R₈ is H.

In some embodiments of Formula (I) or Formula (II), R₉ is selected fromH and C₁₋₆ alkyl. In some embodiments, R₉ is H. In some embodiments, R₉is C₁₋₆ alkyl.

In some embodiments, R₉ is methyl. In some embodiments, R₉ is ethyl. Insome embodiments, R₉ is n-propyl. In some embodiments, R₉ is i-propyl.

In some embodiments of Formula (I) or Formula (II), the carbon atom towhich R₉ is attached is in (S) configuration according toCahn-Ingold-Prelog nomenclature. In some embodiments, the carbon atom towhich R₉ is attached is in (R) configuration according toCahn-Ingold-Prelog nomenclature.

In some embodiments, the stereochemistry at the carbon atom bound to R₉is as shown below:

In some embodiments, the stereochemistry at the carbon atom bound to R₉is as shown below:

In some embodiments of Formula (I) or Formula (II), R₁₀ is H. In someembodiments, R₁₀ is C₂₋₆ alkenyl. In some embodiments, R₁₀ is allyl.

In some embodiments of Formula (I) or Formula (TI), R_(A) is selectedfrom H and methyl. In some embodiments, R_(A) is H.

In some embodiments of Formula (I), L is selected from C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ hydroxyalkyl, C₂₋₆ alkenyl, and —O(CH₂CH₂O)CH₃, whereinthe C₁₋₆ alkyl is optionally substituted with a substituent selectedfrom C₁₋₆ alkoxy, and S(C₁₋₆ alkyl).

In some embodiments of Formula (I) or Formula (II), L is selected fromC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, and C₂₋₆ alkenyl, whereinthe C₁₋₆ alkyl is optionally substituted with a substituent selectedfrom C₁₋₆ alkoxy, and S(C₁₋₆ alkyl). In some embodiments, L is C₁₋₆alkyl. In some embodiments, L is not C₁₋₆ alkyl. In some embodiments, Lis C₁₋₆ haloalkyl. In some embodiments, L is not C₁₋₆ haloalkyl. In someembodiments, L is C₁₋₆ hydroxyalkyl. In some embodiments, L is C₂₋₆alkenyl. In some embodiments, L is C₁₋₆ alkyl substituted with C₁₋₆alkoxy. In some embodiments, L is C₁₋₆ alkyl substituted with S(C₁₋₆alkyl). In some embodiments, L is selected from C₁₋₆ hydroxyalkyl, andC₁₋₆ alkyl substituted with a substituent selected from C₁₋₆ alkoxy, andS(C₁₋₆ alkyl). In some embodiments, L is selected from methyl,fluoromethyl, 2,2,2-trifluoroethyl, trichloromethyl, methylthiomethyl,methoxymethyl, hydroxyethyl, ethoxyethyl, and allyl. In someembodiments, L is fluoromethyl. In some embodiments, L is2,2,2-trifluoroethyl. In some embodiments, L is trichloromethyl. In someembodiments, L is methylthiomethyl. In some embodiments, L ismethoxymethyl. In some embodiments, L is hydroxyethyl. In someembodiments, L is ethoxyethyl. In some embodiments, L is allyl. In someembodiments, L is selected from 2,2,2-trifluoroethyl, trichloromethyl,methylthiomethyl, methoxymethyl, hydroxyethyl, and ethoxyethyl. In someembodiments, L is selected from methylthiomethyl, methoxymethyl,hydroxyethyl, and ethoxyethyl. In some embodiments, L is methyl. In someembodiments, L is not methyl. In some embodiments, L is not3-chloropropyl, ethyl, isopropyl, fluoromethyl, or chloromethyl. In someembodiments, L is not 3-chloropropyl, fluoromethyl, or chloromethyl. Insome embodiments, L is not ethyl or isopropyl.

In some embodiments of Formula (I) or Formula (II), R₁₁ is selected fromH, C₁₋₆ alkyl, C₃₋₅ cycloalkyl, C₁₋₄ haloalkyl, and C₂₋₆ alkenyl,wherein the C₁₋₆ alkyl is optionally substituted with a substituentselected from CN, OH, C₁₋₆ alkoxy, S(C₁₋₆ alkyl), amino, C(O)NH₂, andS(O)₂C₁₋₆ alkyl. In some embodiments, R₁₁ is selected from C₁₋₆ alkyl,C₃₋₅ cycloalkyl, C₁₋₄ haloalkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆alkyl is optionally substituted with a substituent selected from OH,C₁₋₆ alkoxy, S(O)₂C₁₋₆ alkyl, and S(C₁₋₆ alkyl). In some embodiments,R₁₁ is C₁₋₆ alkyl. In some embodiments, R₁₁ is not C₁₋₆ alkyl. In someembodiments, R₁₁ is C₃₋₅ cycloalkyl. In some embodiments, R₁₁ is C₁₋₄haloalkyl. In some embodiments, R₁₁ is C₂₋₆ alkenyl. In someembodiments, R₁₁ is C₁₋₆ alkyl substituted with a substituent selectedfrom OH, C₁₋₆ alkoxy, S(O)₂C₁₋₆ alkyl, and S(C₁₋₆ alkyl). In someembodiments, R₁₁ is C₁₋₆ alkyl substituted with C₁₋₆ alkoxy. In someembodiments, R₁₁ is selected from C₁₋₆ alkyl, C₃₋₅ cycloalkyl, C₂₋₆alkenyl, and C₁₋₆ alkyl substituted with C₁₋₆ alkoxy. In someembodiments, R₁₁ is selected from H, methyl, ethenyl, fluoromethyl,difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl,methylthiomethyl, cyanomethyl, aminomethyl, cyclopropyl, CH₂S(O)₂CH₃,and CH₂C(O)NH₂. In some embodiments, R₁₁ is methyl. In some embodiments,R₁₁ is not methyl. In some embodiments, R₁₁ is ethenyl. In someembodiments, R₁₁ is fluoromethyl. In some embodiments, R₁₁ isdifluoromethyl. In some embodiments, R₁₁ is trifluoromethyl. In someembodiments, R₁₁ is hydroxymethyl. In some embodiments, R₁₁ ismethoxymethyl. In some embodiments, R₁₁ is methylthiomethyl. In someembodiments, R₁₁ is cyanomethyl. In some embodiments, R₁₁ isaminomethyl. In some embodiments, R₁₁ is cyclopropyl. In someembodiments, R₁₁ is CH₂S(O)₂CH₃. In some embodiments, R₁₁ is CH₂C(O)NH₂.In some embodiments, R₁₁ is selected from methyl, ethenyl, CH₂S(O)₂CH₃,methylthiomethyl, fluoromethyl, methoxymethyl, hydroxymethyl, andcyclopropyl. In some embodiments, R₁₁ is selected from methyl,cyclopropyl, ethenyl, and methoxymethyl.

In some embodiments of Formula (I) or Formula (II), the carbon atom towhich R₁₁ is attached is in (S) configuration according toCahn-Ingold-Prelog nomenclature. In some embodiments, the carbon atom towhich R₁₁ is attached is in (R) configuration according toCahn-Ingold-Prelog nomenclature.

In some embodiments, the stereochemistry at the carbon atom bound to R₁₁is as shown below:

In some embodiments, the stereochemistry at the carbon atom bound to R₁₁is as shown below:

In some embodiments of Formula (I) or Formula (II), R₁₂ is selected fromH and methyl. In some embodiments, R₁₂ is methyl. In some embodiments,R₁₂ is H.

In some embodiments of Formula (I) or Formula (II), R₁₁ and R₁₂ togetherwith the carbon atom to which they are attached form a cyclopropyl ring.In some embodiments, R₁₁ is methyl and R₁₂ is methyl. In someembodiments of Formula (I) or Formula (II), Rn is selected from H,fluoro, and methyl. In some embodiments, R₁₃ is fluoro. In someembodiments, R₁₃ is methyl. In some embodiments, R₁₃ is H.

In some embodiments of Formula (I) or Formula (II), R₁₄ is selected fromH, fluoro, and methyl. In some embodiments, R₁₄ is fluoro. In someembodiments, R₁₄ is methyl. In some embodiments, R₁₄ is H.

In some embodiments of Formula (I) or Formula (II), R₁₃ is fluoro andR₁₄ is fluoro. In some embodiments, R₁₃ is methyl and R₁₄ is methyl.

In some embodiments of Formula (I) or Formula (II), R_(B) is selectedfrom H and C(═NH)CH₃. In some embodiments, R_(B) is C(═NH)CH₃. In someembodiments, R_(B) is H.

In some embodiments of Formula (I) or Formula (II), R₁₁ and R_(B)together with the carbon atom to which R₁₁ is attached and the nitrogenatom to which R_(B) is attached form a 6-membered heterocycloalkylcontaining 1-3 heteroatoms selected from N and O, wherein the 6-memberedheterocycloalkyl is optionally substituted with oxo.

In some embodiments of Formula (I) or Formula (II), R₁₁ and R_(B)together with the carbon atom to which R₁₁ is attached and the nitrogenatom to which R_(B) is attached form a ring of any one of the followingformulae:

In some embodiments of Formula (I) or Formula (II), R₁₁ and R_(B)together with the carbon atom to which R₁₁ is attached and the nitrogenatom to which R_(B) is attached form a ring of formula:

In Some Embodiments of Formula (I) or Formula (II):

-   -   R₂ is selected from H, halo, C₁₋₄ haloalkyl, and C₁₋₄        haloalkoxy;    -   R₃ is selected from H, C₁₋₄ haloalkyl, and C(O)C₁₋₄ alkoxy;    -   R₄ is selected from H, halo, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄        haloalkoxy, S(C₁₋₆ alkyl), 6-membered heterocycloalkyl, and        S(O)₂ C₁₋₄ alkyl;    -   R₅ is selected from H and fluoro;    -   R₆ is selected from H, C₃₋₅ cycloalkyl, C₂₋₆ alkenyl, and C₁₋₆        alkyl optionally substituted with a substituent selected from        hydroxyl, C₁₋₄ alkoxy, S(C₁₋₆ alkyl), amino, and NH(5-membered        heteroaryl);    -   R_(7A) is selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄        hydroxyalkyl, and C₂₋₆ alkenyl;    -   R₈ is selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄        hydroxyalkyl, C₁₋₆ alkyl substituted with C₁₋₆ alkoxy, and C₁₋₆        alkyl substituted with 5- to 6-membered heteroaryl, wherein the        5- to 6-membered heteroaryl is optionally substituted with 1, or        2 C₁₋₆ alkyl;    -   R₉ is selected from H, methyl, ethyl, n-propyl and i-propyl;    -   R₁₀ is selected from H and allyl;    -   R_(A) is selected from H and methyl;    -   L is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆        hydroxyalkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆ alkyl is        optionally substituted with a substituent selected from C₁₋₆        alkoxy, and S(C₁₋₆ alkyl);    -   R₁₁ is selected from H, C₁₋₆ alkyl, C₃₋₅cycloalkyl, C₁₋₄        haloalkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆ alkyl is        optionally substituted with a substituent selected from CN, OH,        C₁₋₆ alkoxy, S(C₁₋₆ alkyl), amino, C(O)NH₂, and S(O)₂C₁₋₆ alkyl;    -   R₁₂ is selected from H and methyl;    -   R₁₃ is selected from H, fluoro, and methyl;    -   R₁₄ is selected from H, fluoro, and methyl; and    -   R_(B) is selected from H and C(═NH)CH₃.

In Some Embodiments of Formula (I) or Formula (II):

-   -   R₂ is selected from H, halo, C₁₋₄ haloalkyl, and C₁₋₄        haloalkoxy;    -   R₃ is selected from H, C₁₋₄ haloalkyl, and C(O)C₁₋₄ alkoxy;    -   R₄ is selected from halo, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄        haloalkoxy, S(C₁₋₄ alkyl), 6-membered heterocycloalkyl, and        S(O)₂ C₁₋₄ alkyl;    -   R₅ is selected from H and fluoro;    -   R₆ is selected from H, C₃₋₅ cycloalkyl, C₂₋₆ alkenyl, and C₁₋₆        alkyl optionally substituted with a substituent selected from        hydroxyl, C₁₋₄ alkoxy, S(C₁₋₄ alkyl), amino, and NH(5-membered        heteroaryl);    -   R_(7A) is selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄        hydroxyalkyl, and C₂₋₆ alkenyl;    -   R₈ is selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄        hydroxyalkyl, C₁₋₆ alkyl substituted with C₁₋₆ alkoxy, and C₁₋₆        alkyl substituted with 5- to 6-membered heteroaryl, wherein the        5- to 6-membered heteroaryl is optionally substituted with 1, or        2 C₁₋₆ alkyl;    -   R₉ is selected from H, methyl, ethyl, n-propyl and i-propyl; R₁₀        is selected from H and allyl;    -   R_(A) is selected from H and methyl;    -   L is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆        hydroxyalkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆ alkyl is        optionally substituted with a substituent selected from C₁₋₆        alkoxy, and S(C₁₋₆ alkyl);    -   R₁₁ is selected from H, C₁₋₆ alkyl, C₃₋₅ cycloalkyl, C₁₋₄        haloalkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆ alkyl is        optionally substituted with a substituent selected from CN, OH,        C₁₋₆ alkoxy, S(C₁₋₆ alkyl), amino, C(O)NH₂, and S(O)₂C₁₋₆ alkyl;    -   R₁₂ is selected from H and methyl;    -   R₃ is selected from H, fluoro, and methyl;    -   R₁₄ is selected from H, fluoro, and methyl; and    -   R_(B) is selected from H and C(═NH)CH₃.

In Some Embodiments of Formula (I) or Formula (II):

-   -   R₂ is selected from H, halo, C₁₋₄ haloalkyl, and C₁₋₄        haloalkoxy;    -   R₃ is selected from H, C₁₋₄ haloalkyl, and C(O)C₁₋₄ alkoxy;    -   R₄ is selected from H, halo, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄        haloalkoxy, S(C₁₋₄ alkyl), 6-membered heterocycloalkyl, and        S(O)₂ C₁₋₄ alkyl;    -   R₅ is selected from H and fluoro;    -   R₆ and R_(7A) together with the carbon atoms to which they are        attached and the    -   X atom connecting the two carbon atoms form a ring of any one of        the following formulae:

-   -   R₈ is selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄        hydroxyalkyl, C₁₋₆ alkyl substituted with C₁₋₆ alkoxy, and        C₁₋₆alkyl substituted with 5- to 6-membered heteroaryl, wherein        the 5- to 6-membered heteroaryl is optionally substituted with        1, or 2 C₁₋₆ alkyl;    -   R₉ is selected from H, methyl, ethyl, n-propyl and i-propyl; R₁₀        is selected from H and allyl,    -   R_(A) is selected from H and methyl;    -   L is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆        hydroxyalkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆ alkyl is        optionally substituted with a substituent selected from C₁₋₆        alkoxy, and S(C₁₋₆ alkyl);    -   R₁₁ is selected from H, C₁₋₆ alkyl, C₃₋₅ cycloalkyl, C₁₋₄        haloalkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆ alkyl is        optionally substituted with a substituent selected from CN, OH,        C₁₋₆ alkoxy, S(C₁₋₆ alkyl), amino, C(O)NH₂, and S(O)₂C₁₋₆ alkyl;    -   R₁₂ is selected from H and methyl;    -   R₁₃ is selected from H, fluoro, and methyl;    -   R₁₄ is selected from H, fluoro, and methyl; and    -   R_(B) is selected from H and C(═NH)CH₃.

In Some Embodiments of Formula (I) or Formula (II):

-   -   R₂ is selected from H, halo, C₁₋₄ haloalkyl, and C₁₋₄        haloalkoxy;    -   R₃ is selected from H, C₁₋₄ haloalkyl, and C(O)C₁₋₄ alkoxy;    -   R₄ is selected from halo, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄        haloalkoxy, S(C₁₋₄ alkyl), 6-membered heterocycloalkyl, and        S(O)₂ C₁₋₄ alkyl;    -   R₅ is selected from H and fluoro;    -   R₆ and R_(7A) together with the carbon atoms to which they are        attached and the    -   X atom connecting the two carbon atoms form a ring of any one of        the following formulae:

-   -   R₈ is selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄        hydroxyalkyl, C₁₋₆ alkyl substituted with C₁₋₆ alkoxy, and C₁₋₆        alkyl substituted with 5- to 6-membered heteroaryl, wherein the        5- to 6-membered heteroaryl is optionally substituted with 1, or        2 C₁₋₆ alkyl;    -   R₉ is selected from H, methyl, ethyl, n-propyl and i-propyl;    -   R₁₀ is selected from H and allyl;    -   R_(A) is selected from H and methyl; L is selected from C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, and C₂₋₆ alkenyl,        wherein the C₁₋₆ alkyl is optionally substituted with a        substituent selected from C₁₋₆ alkoxy and S(C₁₋₆ alkyl);    -   R₁₁ is selected from H, C₁₋₆ alkyl, C₃₋₅ cycloalkyl, C₁₋₄        haloalkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆ alkyl is        optionally substituted with a substituent selected from CN, OH,        C₁₋₆ alkoxy, S(C₁₋₆ alkyl), amino, C(O)NH₂, and S(O)₂C₁₋₆ alkyl;    -   R₁₂ is selected from H and methyl;    -   R₁₃ is selected from H, fluoro, and methyl;    -   R₁₄ is selected from H, fluoro, and methyl; and    -   R_(B) is selected from H and C(═NH)CH₃.

In Some Embodiments of Formula (I) or Formula (II):

-   -   R₁ is selected from H and fluoro;    -   R₂ is selected from H, trifluoromethoxy, trifluoromethyl, and        chloro;    -   R₃ is selected from H, trifluoromethyl, and C(═O)(methoxy);    -   W is CR₄;    -   R₄ is selected from H, fluoro, chloro, methylthio, methoxy,        methyl, S(═O)₂(methyl), trifluoromethoxy, and N-morpholino; R₅        is selected from H and fluoro;    -   R₆ is selected from H, cyclopropyl, ethenyl, aminomethyl,        hydroxymethyl, CH₂NH-imidazole, methylthiomethyl, and        methoxymethyl;    -   R_(7A) is selected from H, methyl, trifluoromethyl,        hydroxymethyl, difluoromethyl, and ethenyl;    -   R₈ is selected from H, methyl, 3-fluoropropyl, 2-methoxyethyl,        3-hydroxypropyl, 2-(pyridinyl)ethyl, 2-(imidazolyl)ethyl,        (imidazolyl)methyl, and (oxazolyl)methyl, wherein each        pyridinyl, imidazolyl, and oxazolyl is optionally substituted        with 1 or 2 methyl;    -   R₉ is selected from H and methyl; R₁₀ is selected from H and        allyl;    -   R_(A) is selected from H and methyl;    -   L is selected from methyl, fluoromethyl, 2,2,2-trifluoroethyl,        trichloromethyl, methylthiomethyl, methoxymethyl, hydroxyethyl,        ethoxyethyl, and allyl; R₁₁ is selected from H, methyl, ethenyl,        fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl,        methoxymethyl, methylthiomethyl, cyanomethyl, aminomethyl,        cyclopropyl, CH₂S(O)₂CH₃, and CH₂C(O)NH₂;    -   R₁₂ is selected from H and methyl;    -   R₁₃ is selected from H, fluoro, and methyl;    -   R₁₄ is selected from H, fluoro, and methyl; and    -   R_(B) is selected from H and C(═NH)CH₃.

In Some Embodiments of Formula (I) or Formula (II):

-   -   R₁ is selected from H and fluoro;    -   R₂ is selected from H, trifluoromethoxy, trifluoromethyl and        chloro;    -   R₃ is selected from H, trifluoromethyl, and C(═O)(methoxy);    -   W is CR₄;    -   R₄ is selected from fluoro, chloro, methylthio, methoxy, methyl,        S(═O)₂(methyl), trifluoromethoxy, and N-morpholino;    -   R₅ is selected from H and fluoro;    -   R₆ is selected from H, cyclopropyl, ethenyl, aminomethyl,        hydroxymethyl, CH₂NH-imidazole, methylthiomethyl, and        methoxymethyl;    -   R_(7A) is selected from H, methyl, trifluoromethyl,        hydroxymethyl, difluoromethyl, and ethenyl;    -   R₈ is selected from H, methyl, 3-fluoropropyl, 2-methoxyethyl,        3-hydroxypropyl, 2-(pyridinyl)ethyl, 2-(imidazolyl)ethyl,        (imidazolyl)methyl, and (oxazolyl)methyl, wherein each        pyridinyl, imidazolyl, and oxazolyl is optionally substituted        with 1 or 2 methyl;    -   R₉ is selected from H and methyl; R₁₀ is selected from H and        allyl;    -   R_(A) is selected from H and methyl;    -   L is selected from methyl, fluoromethyl, 2,2,2-trifluoroethyl,        trichloromethyl, methylthiomethyl, methoxymethyl, hydroxyethyl,        ethoxyethyl, and allyl;    -   R₁₁ is selected from H, methyl, ethenyl, fluoromethyl,        difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl,        methylthiomethyl, cyanomethyl, aminomethyl, cyclopropyl,        CH₂S(O)₂CH₃, and CH₂C(O)NH₂;    -   R₁₂ is selected from H and methyl;    -   R₁₃ is selected from H, fluoro, and methyl;    -   R₁₄ is selected from H, fluoro, and methyl; and    -   R_(B) is selected from H and C(═NH)CH₃.        In some embodiments of Formula (I) or Formula (II):    -   R₁ is selected from H and fluoro;    -   R₂ is selected from H, trifluoromethoxy, trifluoromethyl and        chloro;    -   R₃ is selected from H, trifluoromethyl, and C(═O)(methoxy);    -   W is CR₄;    -   R₄ is selected from H, fluoro, chloro, methylthio, methoxy,        methyl, S(═O)₂(methyl), trifluoromethoxy, and N-morpholino;    -   R₅ is selected from H and fluoro;    -   R₆ and R_(7A) together with the carbon atoms to which they are        attached and the X atom connecting the two carbon atoms form a        ring of any one of the following formulae:

-   -   R₈ is selected from H, methyl, 3-fluoropropyl, 2-methoxyethyl,        3-hydroxypropyl, 2-(pyridinyl)ethyl, 2-(imidazolyl)ethyl,        (imidazolyl)methyl, and (oxazolyl)methyl, wherein each        pyridinyl, imidazolyl, and oxazolyl is optionally substituted        with 1 or 2 methyl;    -   R₉ is selected from H, methyl, ethyl, n-propyl and i-propyl;    -   R₁₀ is selected from H and allyl;    -   R_(A) is selected from H and methyl;    -   L is selected from methyl, fluoromethyl, 2,2,2-trifluoroethyl,        trichloromethyl, methylthiomethyl, methoxymethyl, hydroxyethyl,        ethoxyethyl, and allyl;    -   R₁₁ is selected from H, methyl, ethenyl, fluoromethyl,        difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl,        methylthiomethyl, cyanomethyl, aminomethyl, cyclopropyl,        CH₂S(O)₂CH₃, and CH₂C(O)NH₂;    -   R₁₂ is selected from H and methyl,    -   R₁₃ is selected from H, fluoro, and methyl;    -   R₁₄ is selected from H, fluoro, and methyl; and    -   R_(B) is selected from H and C(═NH)CH₃.        In some embodiments of Formula (I) or Formula (II):    -   R₁ is selected from H and fluoro;    -   R₂ is selected from H, trifluoromethoxy, trifluoromethyl and        chloro;    -   R₃ is selected from H, trifluoromethyl, and C(═O)(methoxy);    -   W is CR₄;    -   R₄ is selected from fluoro, chloro, methylthio, methoxy, methyl,        S(═O)₂(methyl), trifluoromethoxy, and N-morpholino;    -   R₅ is selected from H and fluoro;    -   R₆ and R_(7A) together with the carbon atoms to which they are        attached and the X atom connecting the two carbon atoms form a        ring of any one of the following formulae:

-   -   R₈ is selected from H, methyl, 3-fluoropropyl, 2-methoxyethyl,        3-hydroxypropyl, 2-(pyridinyl)ethyl, 2-(imidazolyl)ethyl,        (imidazolyl)methyl, and (oxazolyl)methyl, wherein each        pyridinyl, imidazolyl, and oxazolyl is optionally substituted        with 1 or 2 methyl;    -   R₉ is selected from H and methyl;    -   R₁₀ is selected from H and allyl;    -   R_(A) is selected from H and methyl;    -   L is selected from methyl, fluoromethyl, 2,2,2-trifluoroethyl,        trichloromethyl, methylthiomethyl, methoxymethyl, hydroxyethyl,        ethoxyethyl, and allyl; R₁₁ is selected from H, methyl, ethenyl,        fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl,        methoxymethyl, methylthiomethyl, cyanomethyl, aminomethyl,        cyclopropyl, CH₂S(O)₂CH₃, and CH₂C(O)NH₂;    -   R₁₂ is selected from H and methyl,    -   R₁₃ is selected from H, fluoro, and methyl;    -   R₁₄ is selected from H, fluoro, and methyl; and    -   R_(B) is selected from H and C(═NH)CH₃.

In Some Embodiments of Formula (I) or Formula (II):

-   -   R₁ is fluoro;    -   R₂ is selected from OCF₃, CF₃ and Cl;    -   R₃ is H;    -   R₄ is selected from H, fluoro, chloro, methylthio, methoxy, and        methyl;    -   R₅ is selected from H and fluoro;    -   R₆ is selected from H, cyclopropyl, ethenyl, aminomethyl,        hydroxymethyl,    -   CH₂NH-imidazolyl, methylthiomethyl, and methoxymethyl;    -   R_(7A) is selected from H, methyl, trifluoromethyl,        hydroxymethyl, difluoromethyl, and ethenyl;    -   R₈ is selected from H, methyl, 3-fluoropropyl, 2-methoxyethyl,        3-hydroxypropyl, 2-(pyridinyl)ethyl, 2-(imidazolyl)ethyl,        (imidazolyl)methyl, and (oxazolyl)methyl, wherein each        pyridinyl, imidazolyl, and oxazolyl is optionally substituted        with 1 or 2 methyl;    -   R₉ is selected from H and methyl;    -   R₁₀ is H;    -   R_(A) is H;    -   L is selected from methyl, fluoromethyl, 2,2,2-trifluoroethyl,        trichloromethyl, methylthiomethyl, methoxymethyl, hydroxyethyl,        and ethoxyethyl; R₁₂ is selected from H and methyl; R₁₁ is        selected from methyl, cyclopropyl, ethenyl, and methoxymethyl;    -   R₁₃ is selected from H, fluoro, and methyl;    -   R₁₄ is selected from H, fluoro, and methyl; and    -   R_(B) is H.

In Some Embodiments of Formula (I) or Formula (II):

-   -   R₁ is fluoro;    -   R₂ is selected from OCF₃, CF₃ and Cl;    -   R₃ is H;    -   R₄ is selected from fluoro, chloro, methylthio, methoxy, and        methyl;    -   R₅ is selected from H and fluoro;    -   R₆ is selected from H, cyclopropyl, ethenyl, aminomethyl,        hydroxymethyl, CH₂NH-imidazole, methylthiomethyl, and        methoxymethyl;    -   R_(7A) is selected from H, methyl, trifluoromethyl,        hydroxymethyl, difluoromethyl, and ethenyl;    -   R₈ is selected from H, methyl, 3-fluoropropyl, 2-methoxyethyl,        3-hydroxypropyl, 2-(pyridinyl)ethyl, 2-(imidazolyl)ethyl,        (imidazolyl)methyl, and (oxazolyl)methyl, wherein each        pyridinyl, imidazolyl, and oxazolyl is optionally substituted        with 1 or 2 methyl;    -   R₉ is selected from H, methyl, ethyl, n-propyl and i-propyl;    -   R₁₀ is H;    -   R_(A) is H;    -   L is selected from methyl, fluoromethyl, 2,2,2-trifluoroethyl,        trichloromethyl, methylthiomethyl, methoxymethyl, hydroxyethyl,        and ethoxyethyl;    -   R₁₂ is selected from H and methyl;    -   R₁₁ is selected from methyl, cyclopropyl, ethenyl, and        methoxymethyl;    -   R₁₃ is selected from H, fluoro, and methyl;    -   R₁₄ is selected from H, fluoro, and methyl, and    -   R_(B) is H.

In Some Embodiments of Formula (I) or Formula (II):

-   -   R₁ is selected from H and halo;    -   R₂ is selected from H, OR^(a1), C₁₋₄ haloalkyl and halo;    -   R₃ is selected from H and C₁₋₄ haloalkyl;    -   R₄ is selected from H, halo, S(C₁₋₄ alkyl), C₁₋₆ alkoxy, and        C₁₋₆ alkyl;    -   R₅ is selected from H and halo;    -   R₆ and R_(7A) together with the carbon atoms to which they are        attached and the X atom connecting the two carbon atoms form a        ring of any one of the following formulae:

-   -   wherein x indicates a point of attachment to the ring containing        the W atom and substituted with R₅;    -   R₈ is selected from H, C₁₋₆ alkyl, and C₁₋₄ haloalkyl, wherein        the C₁₋₆ alkyl is optionally substituted with OR^(a3);    -   R₉ is selected from H, methyl, ethyl, n-propyl and i-propyl; R₁₀        is H;    -   R_(A) is H;    -   L is C₁₋₆ alkyl;    -   R₁₁ is selected from selected from C₁₋₆ alkyl, C₃₋₅ cycloalkyl,        C₁₋₄ haloalkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆ alkyl is        optionally substituted with a substituent selected from OH, C₁₋₆        alkoxy, S(O)₂C₁₋₆ alkyl, and S(C₁₋₆ alkyl);    -   R₁₂ is H;    -   R₁₃ is H;    -   R₁₄ is H;    -   R_(B) is H; or    -   R₁₁ and R_(B) together with the carbon atom to which R₁₁ is        attached and the nitrogen atom to which R_(B) is attached form a        ring of formula:

In Some Embodiments of Formula (I) or Formula (II):

-   -   R₁ is selected from H and fluoro;    -   R₂ is selected from H, OCF₃, CF₃ and Cl;    -   R₃ is selected from H and trifluoromethyl;    -   R₄ is selected from H, fluoro, chloro, methylthio, methoxy, and        methyl;    -   R₅ is selected from H and fluoro;    -   R₆ and R_(7A) together with the carbon atoms to which they are        attached and the X atom connecting the two carbon atoms form a        ring of any one of the following formulae:

-   -   wherein x indicates a point of attachment to the ring containing        the W atom and substituted with R₅;    -   R₈ is selected from H, methyl, 3-fluoropropyl, 2-methoxyethyl,        and 3-hydroxypropyl;    -   R₉ is selected from H and methyl;    -   R₁₀ is H;    -   R_(A) is H;    -   L is methyl;    -   R₁₁ is selected from methyl, ethenyl, CH₂S(O)₂CH₃,        methylthiomethyl, fluoromethyl, methoxymethyl, hydroxymethyl,        and cyclopropyl;    -   R₁₂ is H;    -   R₁₃ is H; and    -   R₁₄ is H.

In some embodiments, the compounds of Formula (I) or Formula (II) arecompounds of Formula (Iaa):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein:

R₂ is selected from H, halo, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;

R₄ is selected from H, fluoro, methyl, ethyl, n-propyl, isopropyl,methylthio, and methoxy; and

R₁₁ is selected from H, methyl, ethyl, isopropyl, cyclopropyl,cyclobutyl, cyclopentyl, fluoromethyl, and cyanomethyl.

In some embodiments of Formula (Iaa), R₂ is selected from H, OCF₃, CF₃and Cl. In some embodiments of Formula (Iaa), R₂ is Cl.

In some embodiments of Formula (Iaa), R₄ is selected from H, methyl,methylthio, and methoxy.

In some embodiments of Formula (Iaa), R₁₁ is selected from H, methyl,isopropyl, cyclopropyl, and fluoromethyl.

In some embodiments of Formula (Iaa), R₂ is selected from OCF₃, CF₃ andCl; R₄ is selected from methylthio and methoxy; and R₁₁ is selected frommethyl, cyclopropyl and fluoromethyl. In some embodiments of Formula(Iaa), R₂ is Cl; R₄ is selected from methylthio and methoxy; and R₁₁ isselected from cyclopropyl and methyl. In some embodiments of Formula(Iaa), R₂ is Cl; R₄ is methylthio; and R₁₁ is methyl. In someembodiments of Formula (Iaa), R₂ is Cl; R₄ is methoxy; and R₁₁ ismethyl. In some embodiments of Formula (Iaa), R₂ is Cl; R₄ ismethylthio; and R₁₁ is cyclopropyl. In some embodiments of Formula(Iaa), R₂ is Cl; R₄ is methoxy; and R₁₁ is cyclopropyl.

In some embodiments, the compounds of Formula (I) or Formula (II) arecompounds of Formula (Iab):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein:

R₂ is selected from H, halo, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;

R₈ is selected from H, methyl, n-propyl, n-butyl, 2-chloroethyl,3,3,3-trifluoropropyl, 3-fluoropropyl, 2-methoxyethyl, 2-hydroxypropyl,and 3-hydroxypropyl.

R₁₁ is selected from H, methyl, ethyl, isopropyl, cyclopropyl,cyclobutyl, cyclopentyl, fluoromethyl, and cyanomethyl.

In some embodiments of Formula (Iab), R₂ is selected from H, OCF₃, CF₃and Cl. In some embodiments of Formula (Iab), R₂, is Cl.

In some embodiments of Formula (Iab), R₈ is selected from H, methyl,n-propyl, 3,3,3-trifluoropropyl, 3-fluoropropyl, 2-methoxyethyl, and3-hydroxypropyl.

In some embodiments of Formula (Iab), R₈ is selected from n-propyl,3,3,3-trifluoropropyl, 3-fluoropropyl, and 3-hydroxypropyl.

In some embodiments of Formula (Iab), R₂ is selected from OCF₃, CF₃ andCl; R₈ is selected from 3-fluoropropyl and 3-hydroxypropyl; and R₁ isselected from methyl, cyclopropyl and fluoromethyl. In some embodimentsof Formula (Iab), R₂ is Cl; R₈ is selected from 3-fluoropropyl and3-hydroxypropyl; and R₁₁ is selected from cyclopropyl and methyl. Insome embodiments of Formula (Iab), R₂ is Cl; R₈ is 3-fluoropropyl; andR₁₁ is methyl. In some embodiments of Formula (Iab), R₂ is Cl; R₈ is3-hydroxypropyl; and R₁₁ is methyl. In some embodiments of Formula(Iab), R₂ is Cl; R₈ is 3-fluoropropyl, and R₁₁ is cyclopropyl. In someembodiments of Formula (Iab), R₂ is Cl; R₈ is 3-hydroxypropyl; and R₁₁is cyclopropyl.

In Some Embodiments of Formula (II):

-   -   R₁ is selected from H and halo;    -   R₂ is selected from H, OR^(a1), C₁₋₄ haloalkyl and halo;    -   R₃ is selected from H and C₁₋₄ haloalkyl;    -   R₄ is selected from halo, S(C₁₋₄ alkyl), C₁₋₆ alkoxy, and C₁₋₆        alkyl;    -   R₅ is selected from H and halo;    -   R₆ and R_(7A) together with the carbon atoms to which they are        attached and the X atom connecting the two carbon atoms form a        ring of any one of the following formulae:

-   -   wherein x indicates a point of attachment to the ring containing        the W atom and substituted with R₅;    -   R₈ is selected from H, C₁₋₆ alkyl, and C₁₋₄ haloalkyl, wherein        the C₁₋₆ alkyl is optionally substituted with OR^(a3);    -   R₉ is selected from H, methyl, ethyl, n-propyl and i-propyl;    -   R₁₀ is H;    -   R_(A) is H;    -   L is C₁₋₆ alkyl;    -   R₁₁ is selected from selected from C₁₋₆ alkyl, C₃₋₅ cycloalkyl,        C₁₋₄ haloalkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆ alkyl is        optionally substituted with a substituent selected from OH, C₁₋₆        alkoxy, S(O)₂C₁₋₆ alkyl, and S(C₁₋₆ alkyl);    -   R₁₂ is H;    -   R₁₃ is H;    -   R₁₄ is H;    -   R_(B) is H; or    -   R₁₁ and R_(B) together with the carbon atom to which R₁₁ is        attached and the nitrogen atom to which R_(B) is attached form a        ring of formula:

In some embodiments of Formula (II):

-   -   R₁ is selected from H and fluoro;    -   R₂ is selected from H, OCF₃, CF₃ and Cl;    -   R₃ is selected from H and trifluoromethyl;    -   R₄ is selected from fluoro, chloro, methylthio, methoxy, and        methyl;    -   R₅ is selected from H and fluoro;    -   R₆ and R_(7A) together with the carbon atoms to which they are        attached and the X atom connecting the two carbon atoms form a        ring of any one of the following formulae:

-   -   wherein x indicates a point of attachment to the ring containing        the W atom and substituted with R₅;    -   R₈ is selected from H, methyl, 3-fluoropropyl, 2-methoxyethyl,        and 3-hydroxypropyl;    -   R₉ is selected from H and methyl;    -   R₁₀ is H;    -   R_(A) is H;    -   L is methyl;    -   R₁₁ is selected from methyl, ethenyl, CH₂S(O)₂CH₃,        methylthiomethyl, fluoromethyl, methoxymethyl, hydroxymethyl,        and cyclopropyl;    -   R₁₂ is H;    -   R₁₃ is H;    -   R₁₄ is H;    -   R_(B) is H; or    -   R₁₁ and R_(B) together with the carbon atom to which R₁₁ is        attached and the nitrogen atom to which R_(B) is attached form a        ring of formula:

In Some Embodiments of Formula (II):

-   -   R₁ is selected from H and halo;    -   R₂ is selected from H, halo, C₁₋₄ haloalkyl, and C₁₋₄        haloalkoxy;    -   R₃ is selected from H and C₁₋₄ haloalkyl;    -   R₄ is selected from halo, S(C₁₋₄ alkyl), C₁₋₄ alkoxy, and C₁₋₆        alkyl;    -   R₅ is selected from H and halo;    -   R₆ and R_(7A) together with the carbon atoms to which they are        attached and the X atom connecting the two carbon atoms form a        ring of formula:

-   -   wherein x indicates a point of attachment to the ring containing        the W atom and substituted with R₅;    -   R₈ is selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄        hydroxyalkyl, C₁₋₆ alkyl substituted with C₁₋₆ alkoxy;    -   R₉ is selected from H, methyl, ethyl, n-propyl and i-propyl;    -   R₁₀ is H;    -   R_(A) is H;    -   L is C₁₋₆ alkyl;    -   R₁₁ is selected from C₁₋₆ alkyl, C₃₋₅ cycloalkyl, C₁₋₄        haloalkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆ alkyl is        optionally substituted with a substituent selected from OH, C₁₋₆        alkoxy, S(O)₂C₁₋₆ alkyl, and S(C₁₋₆ alkyl)    -   R₁₂ is H;    -   R₃ is H;    -   R₁₄ is H; and    -   R_(B) is H; or    -   R₁₁ and R_(B) together with the carbon atom to which R₁₁ is        attached and the nitrogen atom to which R_(B) is attached form a        ring of formula:

In Some Embodiments of Formula (II):

-   -   R₁ is selected from H and fluoro;    -   R₂ is selected from H, OCF₃, CF₃ and Cl;    -   R₃ is selected from H and trifluoromethyl;    -   R₄ is selected from fluoro, chloro, methylthio, methoxy, and        methyl;    -   R₅ is selected from 1 and fluoro;    -   R₆ and R_(7A) together with the carbon atoms to which they are        attached and the X atom connecting the two carbon atoms form a        ring of formula:

-   -   wherein x indicates a point of attachment to the ring containing        the W atom and substituted with R₅;    -   R₈ is selected from H, methyl, 3-fluoropropyl, 2-methoxyethyl,        and 3-hydroxypropyl;    -   R₉ is selected from H and methyl;    -   R₁₀ is H;    -   R_(A) is H;    -   L is methyl;    -   R₁₁ is selected from methyl, ethenyl, CH₂S(O)₂CH₃,        methylthiomethyl, fluoromethyl, methoxymethyl, hydroxymethyl,        and cyclopropyl;    -   R₁₂ is H;    -   R₁₃ is H;    -   R₁₄ is H; and    -   R_(B) is H; or    -   R₁₁ and R_(B) together with the carbon atom to which R₁₁ is        attached and the nitrogen atom to which R_(B) is attached form a        ring of formula:

In Some Embodiments of Formula (II):

-   -   R₁ is selected from H and halo;    -   R₂ is selected from H, halo, C₁₋₄ haloalkyl, and C₁₋₄        haloalkoxy;    -   R₃ is selected from H and C₁₋₄ haloalkyl;    -   R₄ is selected from H, halo, S(C₁₋₄ alkyl), C₁₋₄ alkoxy, and        C₁₋₆ alkyl;    -   R₅ is selected from 11 and halo;    -   R₆ and R_(7A) together with the carbon atoms to which they are        attached and the X atom connecting the two carbon atoms form a        ring of formula:

wherein x indicates a point of attachment to the ring containing the Watom and substituted with R₅;

-   -   R₈ is selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄        hydroxyalkyl, C₁₋₆ alkyl substituted with C₁₋₆ alkoxy;    -   R₉ is selected from H, methyl, ethyl, n-propyl and i-propyl;    -   R₁₀ is H;    -   R_(A) is H;    -   L is C₁₋₆ alkyl;    -   R₁₁ is selected from C₁₋₆ alkyl, C₃₋₅ cycloalkyl, C₁₋₄        haloalkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆ alkyl is        optionally substituted with a substituent selected from OH, C₁₋₆        alkoxy, S(O)₂C₁₋₆ alkyl, and S(C₁₋₆ alkyl)    -   R₁₂ is H;    -   R₁₃ is H;    -   R₁₄ is H; and    -   R_(B) is H; or    -   R₁₁ and R_(B) together with the carbon atom to which R₁₁ is        attached and the nitrogen atom to which R_(B) is attached form a        ring of formula:

In Some Embodiments of Formula (II):

-   -   R₁ is selected from H and fluoro;    -   R₂ is selected from H, OCF₃, CF₃ and Cl;    -   R₃ is selected from H and trifluoromethyl;    -   R₄ is selected from H, fluoro, chloro, methylthio, methoxy, and        methyl;    -   R₅ is selected from H and fluoro;    -   R₆ and R_(7A) together with the carbon atoms to which they are        attached and the X atom connecting the two carbon atoms form a        ring of formula:

wherein x indicates a point of attachment to the ring containing the Watom and substituted with R₅;

-   -   R₈ is selected from H, methyl, 3-fluoropropyl, 2-methoxyethyl,        and 3-hydroxypropyl;    -   R₉ is selected from H and methyl;    -   R₁₀ is H;    -   R_(A) is H;    -   L is methyl;    -   R₁₁ is selected from methyl, ethenyl, CH₂S(O)₂CH₃,        methylthiomethyl, fluoromethyl, methoxymethyl, hydroxymethyl,        and cyclopropyl;    -   R₁₂ is selected from H;    -   R₁₃ is H;    -   R₁₄ is H; and    -   R_(B) is H; or    -   R₁₁ and R_(B) together with the carbon atom to which R₁₁ is        attached and the nitrogen atom to which R_(B) is attached form a        ring of formula:

In some embodiments, the compounds of Formula (I) or Formula (II) arecompound of Formula (Ia):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer,wherein R₁, R₂, R₃, R₄, R₅, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R_(A),R_(B), L and W are as described herein.

In some embodiments, the compounds of Formula (I) or Formula (II) arecompound of Formula (Ia-1):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein R₁, R₂, R₃, R₅, R₈, R₉, R₁₀, R₁₁, R₁₂,R₁₃, R₁₄, R_(A), R_(B), and L are as described herein.

In some embodiments, the compounds of Formula (I) or Formula (II) arecompounds of Formula (Ia-2).

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer,wherein R₁, R₂, R₃, R₄, R₅, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R_(A),R_(B), and L are as described herein.

In some embodiments, the compounds of Formula (I) or Formula (II) arecompounds of Formula (Ib-a):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer,wherein R₁, R₂, R₃, R₄, R₅, R₈, R₉, R₁₁, and R₁₂ are as describedherein.

In some embodiments, the compounds of Formula (I) or Formula (II) arecompounds of Formula (Ib):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer,wherein R₁, R₂, R₃, R₄, R₅, R₈, R₉, R₁₁, and R₁₂ are as describedherein.

In some embodiments, the compound of Formula (I) or Formula (II) hasFormula (Ia-3):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer,wherein R₁, R₂, R₃, R₅, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R_(A), R_(B), Land W are as described herein.

In some embodiments, the compounds of Formula (I) or Formula (II) arecompounds of Formula (Ic):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein R₁, R₂, R₃, R₄, R₅, R₉, R₁₁, and R₁₂ areas described herein.

In some embodiments, the compounds of Formula (I) or Formula (II) arecompounds of Formula (Ic-1):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein wherein R₁, R₂, R₃, R₄, R₅, R₉, R₁₁, andR₁₂ are as described herein.

In some embodiments, the compounds of Formula (I) or Formula (II) arecompounds of any one of Formulae (Id)-(Ig):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer;

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer;

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer; and

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer,wherein R₁, R₂, R₃, R₄, R₅, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R_(A),R_(B), L and W are as described herein

In some embodiments, the compounds of Formula (I) or Formula (II) arecompounds of Formula (Ie-1):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer,wherein R₁, R₂, R₃, R₄, R₅, R_(7A), R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄,R_(A), R_(B), L and W are as described herein.

In some embodiments, the compounds of Formula (I) or Formula (II) arecompounds of any one of Formulae (Ih)-(Ik):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer;

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer;

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer; and

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer,wherein R₁, R₂, R₃, R₄, R₅, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R_(A),R_(B), L and W are as described herein.

In some embodiments of any one of Formulae disclosed herein, thefragment:

In some embodiments of any one of Formulae disclosed herein, thefragment

In some embodiments of any one of Formulae disclosed herein, thefragment:

is selected from any one the following fragments:

In some embodiments of any one of Formulae described herein, thefragment:

is selected from any one the following fragments:

In some embodiments of any one of Formulae described herein, thefragment

is selected from any one the following fragments:

In some embodiments of any one of Formulae described herein, thefragment:

In some embodiments of any one of Formulae described herein, thefragment

In some embodiments of any one of the Formulae disclosed herein, thefragment

is selected from any one the following fragments:

In some embodiments, the compound of Formula (I) or Formula (II) is notany one of the following compounds:

In some embodiments, the compound of Formula (I) or Formula (II) is notany one of the following compounds:

or tautomer or a pharmaceutically acceptable salt of the compound ortautomer

In some embodiments, the compounds of Formula (I) or Formula (II) arenot any of the compounds explicitly disclosed in PCT application No.PCT/US2010/052922 (published as WO 2011/047319), PCT application No.PCT/US2012/032994 (published as WO 2012/173689), PCT application No.PCT/US2014/054869 (published as WO 2015/035426), PCT application No.PCT/US2014/054860 (published as WO 2015/035421); or PCT application No.PCT/US2016/022216.

In some embodiments, a compound of Formula (I) or Formula (II) is notcompound 516 disclosed in Table 1 of PCT application No.PCT/US2014/054869 (published as WO 2015/035426). In some embodiments,the compounds of Formula (I) or Formula (II) are not compound 1, 28, 72,81, 82, 85, 86, 97, 120, 137, 150, or 151 disclosed in Table 1 of PCTapplication No. PCT/US2016/022216.

In some embodiments, the compound of Formula (I) or Formula (II) is anyone of the compounds listed in Table 1, or a tautomer thereof or apharmaceutically acceptable salt of the compound or tautomer.

TABLE 1 ESI, m/z # Structure [M + H]+ 2

612.6 3

579 4

594.7 6

592.7 7

606.7 8

594.7 9

624.27 10

636.32 11

632.6 12

624.7 13

650.6 14

578 15

608.7 16

647.13 17

581 18

582 19

647 20

599 21

665 22

610.6 23

596 24

606.6 25

624.6 26

592.6 27

610.6 28

612.6 29

633.7 30

590.6 31

590.6 32

594.6 33

605.17 34

609.16 35

598.6 36

604.6 37

608.6 38

608.6 39

594.6 40

596.6 41

629.21 42

639.3 43

650.6 44

650.6 45

593.6 46

611.6 47

594.5 48

593.5 49

611.4 50

593.5 51

611.5 52

637.2 53

609.2 54

610.6 55

628.6 56

606.6 57

624.6 58

647.2 59

625.2 60

592 61

600 62

608. 63

647.1 64

665.1 65

586.6 66

648.6 67

666.6 68

608.6 69

626.6 70

582.6 71

608.6 72

626.6 73

584.6 74

602.6 75

612.6 76

570 77

588 78

620.6 79

608.5 80

606.4 81

624.4 82

606.2 83

594.5 84

616.4 85

627.7 86

636.5 87

604.4 88

630 89

622.4 90

614.4 91

604.4 92

596.5 93

584 94

602 95

612 96

596.5 97

614.5 98

620.4 99

610.5 100

600.4 101

590.5 102

620.4 103

596.5 104

610.5 105

600.4 106

606.4 107

602.4 108

624.5 109

606.5 110

566.4 111

596.5 112

584 113

600 114

602 115

638.5 116

654.5 117

670.5 118

686.1 119

592.5 120

664.5 121

622.5 122

640.5 123

632.5 124

618.5 125

618 126

656.5 127

628.5 128

650.5 129

660.5 130

620.4 131

578.5 132

582.5 133

598.5 134

608.5 135

628.5 136

600.5 137

624.5 138

594.5 139

628.5 140

614.4 141

628.5 142

614.5 143

604.4 144

590.5 145

578.4 146

590.4 147

604.5 148

596.5 149

604.5 150

610.5 151

608.5 152

610 153

594.5 154

617.5 155

603.4 156

635.5 157

621.5 158

594.5 159

602.4 160

622.5 161

579 162

626 163

630 164

618.5 165

661.7 166

622.6 167

637.2 168

626 169

622.5 170

628.3 171

640.6 172

608.4 173

622.5 174

626.4 175

626.6 176

646.0 177

614.4 178

632.3 179

597 180

646.5 181

664.5 182

650.4 183

610.4 184

622.5 185

727.4 186

628.4 187

608.4 188

614.4 189

596.4 190

656.6 191

674.6 192

593.4 193

644.5 194

686.5 195

672 196

690 197

702 198

718.4 199

702.5 200

638.5 201

656.5 202

684.5 203

672.5 204

626.5 205

644.5 206

634 207

668 208

686 209

656.5 210

668.5 211

652 212

652 213

752 214

722.4 215

710.4 216

740.3 217

718 218

611.3 219

618.7 220

604.4 221

662.7 222

638.8 223

672.8 224

656.8 225

728.6 226

635.3 227

649.2 228

n/a 229

n/a 230

644.8 231

742 232

606.4 233

756 234

698.4 235

682.4 236

660.7 237

674.5 238

686.8 239

632.5 240

656.4 241

736.4 242

732.4 243

664.6 244

634.4 245

652.4 246

640.4 247

654.4 248

619.4 249

653.5 250

680.85 251

698.84 252

714.84 253

606.4 254

606.4 255

690.4 256

632.4 257

632.4 258

686.5 259

618.4 260

682.1 261

697 262

686 263

700 264

652 265

590.4 266

604.4 267

592.4 268

658.4 269

636.4 270

690.4 271

610.4 272

682.3 273

696.3 274

668.3 275

682.4 276

638.4 277

650 278

673 279

646.4 280

708.7 281

644.4 282

695 283

606.4 284

670.3 285

670.7 286

698.5 287

608.4 288

700 289

607.4 290

650 291

598.4 292

714 293

668

In some embodiments, the present disclosure provides any one ofcompounds listed in Table 1a, or a tautomer thereof or apharmaceutically acceptable salt of the compound or tautomer.

TABLE 1a # Structure 294

295

296

297

298

300

305

306

307

308

309

310

311

312

313

314

315

316

In some embodiments, the present disclosure provides any one ofcompounds listed in Table 1b, or a tautomer thereof or apharmaceutically acceptable salt of the compound or tautomer.

TABLE 1b ESI, m/z # Structure [M + H]+ 317

626.8 318

626.8 319

640.3 320

652.3 321

666.4 322

700.4 323

690.4 325

670 326

740 327

712 328

686 329

732 330

694 331

698 332

696 333

724 334

678 335

678.5 336

716 337

758 338

742 339

670.5 340

618 4 341

652.3 342

726 343

664 344

710 346

680 347

673.8 348

636 349

698 350

728 351

744 352

620.3 353

666.2 355

682 356

622.3 357

622 1 358

623.3 360

634 362

666 363

578 364

638 365

664 366

664 369

648 370

574.4 377

570.5

In some embodiments, the present disclosure relates to a compound or atautomer thereof, or a pharmaceutically acceptable salt of said compoundor tautomer that binds the ribosome. In some embodiments, the ribosomeis a bacterial ribosome.

In some embodiments, the present disclosure relates to a pharmaceuticalcomposition comprising a compound disclosed herein, or a tautomerthereof, or a pharmaceutically acceptable salt of said compound ortautomer, and a pharmaceutically acceptable carrier. In someembodiments, the present disclosure relates to a compound or a tautomerthereof, or a pharmaceutically acceptable salt of said compound ortautomer disclosed herein and a means for delivery.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of or delaying the onset of adisease state in a human or animal comprising administering to the humanor animal in need thereof an effective amount of a compound disclosedherein, or a tautomer thereof, or a pharmaceutically acceptable salt ofsaid compound or tautomer.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection in a human or animal comprising administering to thehuman or animal an effective amount of a compound disclosed herein, or atautomer thereof, or a pharmaceutically acceptable salt of said compoundor tautomer.

In some embodiments, the present disclosure relates to use of a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, in the manufacture of amedicament for treating, preventing, reducing the risk of, or delayingthe onset of, a microbial infection in a human or animal. In anotheraspect, the present disclosure relates to a compound for use in themanufacture of a medicament for treating a microbial infection in asubject, wherein the compound is selected from a compound of the presentdisclosure, or a tautomer thereof, or a pharmaceutically acceptable saltof said compound or tautomer.

In some embodiments, the present disclosure relates to a compound foruse in the manufacture of a medicament for preventing a microbialinfection in a subject, wherein the compound is selected from a compoundof the present disclosure, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer.

In some embodiments, the present disclosure relates to a compound foruse in the manufacture of a medicament for reducing the risk of amicrobial infection in a subject, wherein the compound is selected froma compound of the present disclosure, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer.

In some embodiments, the present disclosure relates to a compound foruse in the manufacture of a medicament for delaying the onset of amicrobial infection in a subject, wherein the compound is selected froma compound of the present disclosure, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer.

In some embodiments, the present disclosure relates to a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, for use in treating,preventing, reducing the risk of, or delaying the onset of a microbialinfection in a human or animal.

In some embodiments, the present disclosure relates to a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, for use in treating amicrobial infection in a human or animal.

In some embodiments, the present disclosure relates to a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, for use in preventing amicrobial infection in a human or animal.

In some embodiments, the present disclosure relates to a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, for use in reducing therisk of a microbial infection in a human or animal.

In some embodiments, the present disclosure relates to a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, for use in delaying theonset of a microbial infection in a human or animal.

In some embodiments, a microbial infection as described herein is causedby one or more microoganisms selected from the group consisting of:Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae,Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species,and Escherichia coli. This group of microoganisms can be referred togenerally as the ESKAPE pathogens. In some embodiments, the microbialinfection is caused by a microorganism which is resistant to at leastone antibacterial. For example, the microorganism can be classified asmulti-drug resistant or extremely-drug resistant.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection in a human or animal comprising administering to thehuman or animal an effective amount of a compound or a tautomer thereof,or a pharmaceutically acceptable salt of said compound or tautomer,wherein said microbial infection is caused by one or more of thefollowing microorganisms: Acinetobacter spp. (Acinetobacter baumanni),Bacteroides distasonis, Bacteroides fragilis, Bacteroides ovatus,Bacteroides thetaiotaomicron, Bacteroides uniformis. Bacteroidesvulgatus, Citrobacter freundii, Citrohacter koser, Chlamydiatrachonatis, Chlamydia psittaci, Chlamydia pneumoniae, Chlamydiapecorum, Hlamydia suis, Chlamydia muridarum, Chlamydophila psittaci,Chlamdophila pneumoniae, Chlamydophila pecorum, Clostridiumclostridioforme, Clostridium perfringens, Enterobacter aerogenes,Enterobacter cloacae, Enterococcus faecalis, Enterococcus spp.(vancomycin susceptible and resistant isolates), Escherichia coli(including ESBL and KPC producing isolates), Eubacterium lentum,Fusobacterium spp., Haemophilus influenza (including beta-lactamasepositive isolates), Haemophilus parainfluenzae, Klebsiella pneumoniae(including ESBL and KPC producing isolates), Klebsiella oxytoca(including ESBL and KPC producing isolates), Legionella pneumophiliaMoraxella catarrhalis, Morganella morganii, Mycoplasma spp., Neisseriagonorrhoeae (including Neisseria gonorrhoeae ATCC49266, Neisseriagonorrhoeae 255123, Neisseria gonorrhoeae 255124, Neisseria gonorrhoeae255125. Neisseria gonorrhoeae 255126, Neisseria gonorrhoeae 255127,Neisseria gonorrhoeae J9104300210, Neisseria gonorrhoeae J9107400107,Neisseria gonorrhoeae J9109510210, Neisseria gonorrhoeae J9108110210),Peptostreptococcus spp., Porphyromonas asaccharolytica, Prevotellabivia, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri,Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens,Streptococcus anginosus, Staphylococcus aureus (methicillin susceptibleand resistant isolates), Staphylococcus epidermidis (methicillinsusceptible and resistant isolates), Stenotrophomonas maltophilia,Streptococcus agalactiae, Streptococcus constellatus, Streptococcuspneumoniae (penicillin susceptible and resistant isolates),Streptococcus pyogenes, or Streptococcus pyogenes.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection in a human or animal comprising administering to thehuman or animal an effective amount of a compound or a tautomer thereof,or a pharmaceutically acceptable salt of said compound or tautomer,wherein said infection is caused by or involves one or moremicroorganisms selected from: Acinetobacter spp. (Acinetobacterbaumanni), Bacteroides distasonis, Bacteroides fragilis, Bacteroidesovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroidesvulgatus, Citrobacter freundii, Citrobacter koser, Chlamydiatrachomatis, Chlamydia psittaci, Chlamydia pneumoniae, Chlamydiapecorum, hlamydia suis, Chlamydia muridarum, Chlamydophila psittaci,Chlamydophila pneumoniae, Chlamydophila pecorum, Clostridiumclostridioforme, Clostridium perfringens, Enterobacter aerogenes,Enterobacter cloacae, Enterococcus faecalis, Enterococcus spp.,Escherichia coli, Eubacterium lentum, Fusobacterium spp., Halemophilusinfluenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae,Klebsiella oxytoca, Legionella pneumophilia, Moraxella catarrhalis,Morganella morganii, Mycoplasma spp., Neisseria gonorrhoeae,Peptostreptococcus spp., Porphyromonas asaccharolytica, Prevotellabivia, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri,Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens,Streptococcus anginosus, Staphylococcus aureus, Staphylococcusepidermidis, Stenotrophomonas maltophilia, Streptococcus agalactiae,Streptococcus constellatus, Streptococcus pneumoniae, Streptococcuspyogenes, and Streptococcus pyogenes.

In some embodiments, the present disclosure relates to a method whereinsaid infection is caused by or involves one or more of aerobic andfacultative gram-positive microorganisms selected from: Staphylococcusaureus, Streptococcus pneumoniae, Enterococcus spp., Streptococcusagalactiae, Streptococcus pyogenes, and Staphylococcus epidermidis.

In some embodiments, the present disclosure relates to a method whereinsaid infection is caused by or involves one or more of aerobic andfacultative gram-negative microorganisms selected from: Escherichiacoli, Haemophilus influenzae, Klebsiella pneumoniae, Citrobacterfreundii, Chlamydia trachomatis, Chlamydia psittaci, Chlamydiapneumoniae, Chlamydia pecorum, hlamydia suis, Chlamydia muridarum,Chlamydophila psittaci, Chlamydophila pneumoniae, Chlamydophila pecorum,Enterobacter aerogenes, Enterobacter cloacae, Morganella morganii,Neisseria gonorrhoeae, Serratia marcescens, Pseudomonas aeruginosa,Acinetobacter baumanni, Moraxella catarrhalis, Proteus mirabilis,Citrobacter koseri, Haemophilus parainfluenzae, Klebsiella oxytoca,Proteus vulgaris, Providencia rettgeri, and Providencia stuartii.

In some embodiments, the present disclosure relates to a method whereinthe infection is caused by or involves one or more anaerobicmicroorganisms: Bacteroides fragilis, Bacteroides distasonis,Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis,Clostridium clostridioforme, Eubacterium lentum, Peptostreptococcus spp.Porphyromonas asaccharolytica, Prevotella bivia, Bacteroides vulgatus,Clostridium perfringens, and Fusobacterium spp.

In some embodiments, the present disclosure relates to a method, whereinthe microorganism Enterococcus spp. is selected from vancomycinsusceptible isolate and vancomycin resistant isolate.

In some embodiments, the present disclosure relates to a method whereinthe microorganism Escherichia coli is selected from extended spectrumbeta-lactamase (ESBL) producing isolate and Klebsiella pneumoniaecarbapenemase (KPC) producing isolate.

In some embodiments, the present disclosure relates to a method whereinthe microorganism Haemophilus influenzae is a beta-lactamase positiveisolate.

In some embodiments, the present disclosure relates to a method whereinthe microorganism Klebsiella pneumoniae is selected from extendedspectrum beta-lactamase (ESBL) producing isolate and Klebsiellapneumoniae carbapenemase (KPC) producing isolate.

In some embodiments, the present disclosure relates to a method whereinthe microorganism Klebsiella oxytoca selected from extended spectrumbeta-lactamase (ESBL) producing isolate and Klebsiella pneumoniaecarbapenemase (KPC) producing isolate.

In some embodiments, the present disclosure relates to a method whereinthe microorganism Staphylococcus aureus is selected from methicillinsusceptible isolate and methicillin resistant isolate.

In some embodiments, the present disclosure relates to a method whereinthe microorganism Staphylococcus epidermidis is selected frommethicillin susceptible isolate and methicillin resistant isolate.

In some embodiments, the present disclosure relates to a method whereinthe microorganism Streptococcus pneumoniae is selected from penicillinsusceptible isolate and penicillin resistant isolate.

In some embodiments, the present disclosure relates to a method whereinthe microorganism Neisseria gonorrhoeae is selected from susceptible andresistant isolates, including, for example, ceftriaxone-resistant,ciprofloxacin-resistant and azithromycin-resistant isolates.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection in a human or animal comprising administering to thehuman or animal an effective amount of a compound or a tautomer thereof,or a pharmaceutically acceptable salt of said compound or tautomer,wherein said microbial infection is caused by or involves one or moremicroorganisms which are capable of being used as biological weapons,e.g., wherein the one or more microorganisms are selected from Bacillusanthracis and Multi Drug Resistant (MDR) anthracis, Franciscellatularensis, Yersinia pestis, Burkholderia mallei, and Burkholderiapseudomallei.

In some embodiments, the present disclosure pertains, at least in part,to a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, or apharmaceutical composition thereof, for use in a method of preventing amicrobial, e.g., bacterial, infection in a subject, wherein theinfection is caused by or involves one or more microorganisms which arecapable of being used as biological weapons, e.g., wherein the one ormore microorganisms are selected from Bacillus anthracis and Multi DrugResistant (MDR) anthracis, Franciscella tularensis, Yersinia pestis,Burkholderia mallei, and Burkholderia pseudomallei.

In some embodiments, the present disclosure pertains, at least in part,to a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, or apharmaceutical composition thereof, for use in a method of reducing therisk of a microbial, e.g., bacterial, infection in a subject, whereinthe infection is caused by or involves one or more microorganisms whichare capable of being used as biological weapons, e.g., wherein the oneor more microorganisms are selected from Bacillus anthracis and MultiDrug Resistant (MDR) anthracis, Franciscella tularensis, Yersiniapestis, Burkholderia mallei, and Burkholderia pseudomallei.

In some embodiments, the present disclosure pertains, at least in part,to a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, or apharmaceutical composition thereof, for use in a method of delaying theonset of a microbial, e.g., bacterial, infection in a subject, whereinthe infection is caused by or involves one or more microorganisms whichare capable of being used as biological weapons, e.g., wherein the oneor more microorganisms are selected from Bacillus anthracis and MultiDrug Resistant (MDR) anthracis, Franciscella tularensis, Yersiniapestis, Burkholderia mallei, and Burkholderia pseudomallei.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection in a human or animal comprising administering to thehuman or animal an effective amount of a compound disclosed herein, or atautomer thereof, or a pharmaceutically acceptable salt of said compoundor tautomer, or use of a compound disclosed herein, or a tautomerthereof, or a pharmaceutically acceptable salt of said compound ortautomer, in the manufacture of a medicament for treating, preventing,reducing the risk of, or delaying the onset of a microbial infection ina human or animal, wherein the microbial infection is selected from thegroup consisting of: a skin infection, a Gram positive infection, a Gramnegative infection, nosocomial pneumonia, community acquired pneumonia,post-viral pneumonia, hospital acquired pneumonia/ventilator associatedpneumonia, a respiratory tract infection such as chronic respiratorytract infection (CRTI), acute pelvic infection, a complicated skin andskin structure infection, a skin and soft tissue infection (SSTI)including uncomplicated skin and soft tissue infections (uSSTI)s andcomplicated skin and soft tissue infections, an abdominal infection, acomplicated intra-abdominal infection, a urinary tract infection,bacteremia, septicemia, endocarditis, an atrio-ventricular shuntinfection, a vascular access infection, meningitis, surgicalprophylaxis, a peritoneal infection, a bone infection, a jointinfection, a methicillin-resistant Staphylococcus aureus infection, avancomycin-resistant Enterococci infection, a linezolid-resistantorganism infection, gonorrhea, Chlamydia, and tuberculosis.

The compounds of the present disclosure can be used, for example for thetreatment of patients with moderate to severe infections, which may becaused by susceptible isolates of the indicated microorganisms.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of acomplicated intra-abdominal infection in a human or animal comprisingadministering to the human or animal an effective amount of a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, or to the use of acompound disclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, in the manufacture of amedicament for treating, preventing, reducing the risk of, or delayingthe onset of a complicated intra-abdominal infection in a human oranimal.

In some embodiments, the complicated intra-abdominal infection isselected from polymicrobial infections such as abscess due toEscherichia coli, Clostridium clostridioforme, Eubacterium lentum,Peptostreptococcus spp., Bacteroides fragilis, Bacteroides distasonis,Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis,Streptococcus anginosus, Streptococcus constellatus, Enterococcusfaecalis, Proteus mirabilis, or Clostridium perfringens.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of acomplicated skin and skin structure infection (cSSSI, also known asacute bacterial skin and skin structure infections or ABSSSI) in a humanor animal comprising administering to the human or animal an effectiveamount of a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, or to theuse of a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, in themanufacture of a medicament for treating, preventing, reducing the riskof, or delaying the onset of a complicated skin and skin structureinfection

In some embodiments, the complicated skin and skin structure infectionis selected from diabetic foot infections without osteomyelitis due toStaphylococcus aureus (methicillin susceptible and resistant isolates),Streptococcus agalactiae, Streptococcus pyogenes, Escherichia coli,Klebsiella pneumoniae, Proteus mirabilis, Bacteroides fragilis,Peptostreptococcus species, Porphyromonas asaccharolytica, or Prevotellabivia.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of acommunity acquired pneumonia (CAP) in a human or animal comprisingadministering to the human or animal an effective amount of a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, or to the use of acompound disclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, in the manufacture of amedicament for treating, preventing, reducing the risk of, or delayingthe onset of community acquired pneumonia.

In some embodiment, the community acquired pneumonia is due toStreptococcus pneumoniae (penicillin susceptible and resistant isolates)including cases with concurrent bacteremia, Haemophilus influenzae(including beta-lactamase positive isolates), Moraxella catarrhalis, oratypical bacteria like Mycoplasma spp.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of acomplicated urinary tract infection (cUTI) in a human or animalcomprising administering to the human or animal an effective amount of acompound disclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, or to the use of acompound disclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, in the manufacture of amedicament for treating, preventing, reducing the risk of, or delayingthe onset of a complicated urinary tract infection.

In some embodiment, the complicated urinary tract infection is selectedfrom pyelonephritis due to Escherichia coli, concurrent bacteremia, orKlebsiella pneumoniae.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of anacute pelvic infection in a human or animal comprising administering tothe human or animal an effective amount of a compound disclosed herein,or a tautomer thereof, or a pharmaceutically acceptable salt of saidcompound or tautomer, or to the use of a compound disclosed herein, or atautomer thereof, or a pharmaceutically acceptable salt of said compoundor tautomer, in the manufacture of a medicament for treating,preventing, reducing the risk of, or delaying the onset of a acutepelvic infection.

In some embodiments, the acute pelvic infection is selected frompostpartum endomyometritis, septic abortion and post-surgicalgynecologic infections and the infection is due to a microorganismselected from Streptococcus agalactiae, Escherichia coli, Bacteroidesfragilis, Porphyromonas asaccharolytica, Peptostreptococcus spp., andPrevotella bivia.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of ahospital acquired pneumonia (HAP)/ventilator associated pneumonia (VAP)in a human or animal comprising administering to the human or animal aneffective amount of a compound disclosed herein, or a tautomer thereof,or a pharmaceutically acceptable salt of said compound or tautomer, orto the use of a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, in themanufacture of a medicament for treating, preventing, reducing the riskof, or delaying the onset of hospital acquired pneumonia/ventilatorassociated pneumonia.

In some embodiments, the hospital acquired pneumonia/ventilatorassociated pneumonia is due to a microorganism selected fromStreptococcus pneumoniae (penicillin susceptible and resistantisolates), Staphylococcus aureus (methicillin susceptible and resistantisolates), Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacterspp., Stenotrophomonas maltophilia. Haemophilus influenzae (includingbeta-lactamase positive isolates), and Legionella pneumophilia.

The compounds or tautomers or pharmaceutically acceptable salts of saidcompounds or tautomers of the present disclosure may also be useful forthe prevention, prophylaxis, or reduction of surgical site infections.In some embodiments, the compounds or tautomers or pharmaceuticallyacceptable salts of said compounds or tautomers of the presentdisclosure are useful following elective colorectal surgery.

Appropriate specimens for bacteriological examination should be obtainedin order to isolate and identify the causative organisms and todetermine their susceptibility to the compounds of the presentdisclosure. Therapy with the compounds or tautomers or pharmaceuticallyacceptable salts of said compounds or tautomers of the presentdisclosure may be initiated empirically before results of these testsare known; once results become available, antimicrobial therapy shouldbe adjusted accordingly.

To reduce the development of drug-resistant bacteria and maintain theeffectiveness of the compounds or tautomers or pharmaceuticallyacceptable salts of said compounds or tautomers of the presentdisclosure and other antibacterial drugs, the compounds or tautomers orpharmaceutically acceptable salts of said compounds or tautomers shouldbe used only to treat or prevent infections that are proven or stronglysuspected to be caused by susceptible bacteria. When culture andsusceptibility information are available, they should be considered inselecting or modifying antibacterial therapy. In the absence of suchdata, local epidemiology and susceptibility patterns may contribute tothe empiric selection of therapy.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection due to an aerobic or facultative gram-positivemicroorganism in a human or animal comprising administering to the humanor animal an effective amount of a compound disclosed herein, or atautomer thereof, or a pharmaceutically acceptable salt of said compoundor tautomer, or to the use of a compound disclosed herein, or a tautomerthereof, or a pharmaceutically acceptable salt of said compound ortautomer, in the manufacture of a medicament for treating, preventing,reducing the risk of, or delaying the onset of a microbial infection dueto an aerobic or facultative gram-positive microorganism.

In some embodiments, the aerobic or facultative gram-positivemicroorganism is selected from: Staphylococcus aureus (methicillinsusceptible and resistant isolates), Streptococcus pneumoniae(penicillin susceptible and resistant isolates), Enterococcus spp.(vancomycin susceptible and resistant isolates), Streptococcusagalactiae, Streptococcus pyogenes, and Staphylococcus epidermidis(methicillin susceptible and resistant isolates).

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection due to an aerobic and facultative gram-negativemicroorganism in a human or animal comprising administering to the humanor animal an effective amount of a compound disclosed herein, or atautomer thereof, or a pharmaceutically acceptable salt of said compoundor tautomer, or to the use of a compound disclosed herein, or a tautomerthereof, or a pharmaceutically acceptable salt of said compound ortautomer, in the manufacture of a medicament for treating, preventing,reducing the risk of, or delaying the onset of a microbial infection dueto an aerobic or facultative gram-positive microorganism.

In some embodiments, the aerobic and facultative gram-negativemicroorganism is selected from: Escherichia coli [including extendedspectrum beta-lactamase (ESBL) and Klebsiella pneumomiae (KPC) producingisolates), Haemophilus influenzae (including Beta-lactamase positiveisolates), Klebsiella pneumoniae (including ESBL and KPC producingisolates), Citrobacter freundii, Enterobacter aerogenes, Enterobactercloacae, Morganella morganii, Serratia marcescens, Pseudomonasaeruginosa, Acinetobacter baumannii, Moraxella catarrhalis, Proteusmirabilis, Citrobacter koseri, Haemophilus parainfluenzae, Klebsiellaoxytoca (including ESBL and KPC producing isolates), Proteus vulgaris,Providencia rettgeri, and Providencia stuartii.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection due to an anaerobic microorganism in a human oranimal comprising administering to the human or animal an effectiveamount of a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, or to theuse of a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, in themanufacture of a medicament for treating, preventing, reducing the riskof, or delaying the onset of a microbial infection due to an anaerobicmicroorganism.

In some embodiments, the anaerobic microorganism is selected from:Bacteroides fragilis, Bacteroides distasonis, Bacteroides ovatus,Bacteroides thetaiotaomicron, Bacteroides uniformis, Clostridiumclostridioforme, Eubacterium lentum, Peptostreptococcus species,Porphyromonas asaccharolytica, Prevotella bivia, Bacteroides vulgates,Clostridium perfringens, and Fusobacterium spp.

In some embodiments, the present disclosure relates to a method oftreating or reducing the risk of a microbial infection in a human oranimal comprising administering to the human or animal an effectiveamount of a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, or to theuse of a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, in themanufacture of a medicament for treating, preventing, reducing the riskof, or delaying the onset of a microbial infection.

In some embodiments, the microorganism is Legionella pneumophila.

In some embodiments, the microorganism Enterococcus spp. is selectedfrom vancomycin susceptible isolate and vancomycin resistant isolate. Insome embodiments, the microorganism Escherichia coli is selected fromextended spectrum beta-lactamase (ESBL) producing isolate and Klebsiellapneumoniae carbapenemase (KPC) producing isolate. In some embodiments,the microorganism Haemophilus influenzae is a beta-lactamase positiveisolate. In some embodiments, the microorganism Klebsiella pneumoniae isselected from extended spectrum beta-lactamase (ESBL) producing isolateand Klebsiella pneumoniae carbapenemase (KPC) producing isolate. In someembodiments, the microorganism Klebsiella oxytoca selected from extendedspectrum beta-lactamase (ESBL) producing isolate and Klebsiellapneumoniae carbapenemase (KPC) producing isolate. In some embodiments,the microorganism Staphylococcus aureus is selected from methicillinsusceptible isolate and methicillin resistant isolate. In someembodiments, the microorganism Staphylococcus epidermidis is selectedfrom methicillin susceptible isolate and methicillin resistant isolate.In some embodiments, the microorganism Streptococcus pneumoniae isselected from penicillin susceptible isolate and penicillin resistantisolate.

In some embodiments, a method or use disclosed herein is a method or useto treat a subject that would be subjected to a surgical or invasivemedical procedure Such a subject can be considered to be in need of themethods of treating, reducing the risk of or preventing the infectiondue to a surgical procedure or an invasive medical procedure. Such asubject can also be considered to be in need of peri-operativeprophylaxis.

In some embodiments, the present disclosure relates to a method, use, orcompound disclosed herein, wherein the amount of compound or a tautomerthereof, or a pharmaceutically acceptable salt of said compound ortautomer comprises from 0.1 mg to 1500 mg.

In some embodiments, the present disclosure relates to a method, use, orcompound disclosed herein wherein the compound, or a tautomer thereof,or a pharmaceutically acceptable salt of said compound or tautomer, isadministered otically, ophthalmically, nasally, orally, parenterally,topically, or intravenously.

In some embodiments, the present disclosure relates to a method ofsynthesizing a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer.

In some embodiments, the present disclosure relates to a medical devicecontaining a compound disclosed herein or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer. In someembodiments, the device is a stent.

3. Synthesis of the Compounds of the Disclosure

The compounds of the present disclosure can be synthesized by using artrecognized techniques, such as those described in US 2012-0220566, WO2012/173689, or PCT/US2014/054869, the contents of each of which areincorporated herein by reference in their entireties. The compounds thusobtained can be further purified, for example, by flash columnchromatography, high performance liquid chromatography, crystallization,or any known purification method.

In one embodiment, compounds of the present disclosure can besynthesized according to the synthetic Schemes 1-3 below:

Referring to Scheme 1:

Step 1: (S)-(−)-2-methyl-2-propanesulfinamide (1) and aldehyde (2) arereacted to yield (3). In some embodiments, the reaction is carried outis a solvent (e.g., dichloromethane). In some embodiments, the reactionis carried out at a temperature from about 30° C. to about 50° C. (e.g.,at 40° C.). In some embodiments, the reaction is carried out in thepresence of a base (e.g., cesium carbonate).

Step 2: Intermediate (3) is reacted with allyl bromide to obtain (4). Insome embodiments, the reaction is carried out in a solvent (e.g.,N—N′-dimethylformamide). In some embodiments, the reaction is carriedout in the presence of activated zinc.

Step 3: Intermediate (4) is reacted with iodoacrylate (5) to yield (6).In some embodiments, the reaction is carried out in the presence of acatalyst. In some embodiments, the catalyst is Pd(PPh₃)₄.

Step 4: Intermediate (6) is reacted with a base to afford (7). In someembodiments, the base is cesium carbonate. In some embodiments, thereaction is carried out in a solvent (e.g., N—N′-dimethylformamide).

Step 5: Intermediate (7) is reacted with a reducing agent to obtain (8).In some embodiments, the reducing agent is DIBAL.

Step 6. Intermediate (8) is reacted with azide-containing reagent toobtain (9). In some embodiments, the azide-containing reagent isdiphenylphosphoryl azide (DPPA). In some embodiments, the reaction iscarried out in the presence of a base (e.g., DBU). In some embodiments,the reaction is carried out at a temperature from about 40° C. to about120° C. (e.g., at about 80° C.).

Step 7: Intermediate (9) is treated with an acid (e.g., HCl)) to removetert-butylsulfinyl auxiliary group. The resultant NH-containingintermediate is reacted with a protecting group (e.g., Cbz-Cl) to yieldintermediate (10).

Step 8: Intermediate (10) is reacted with triphenylphosphine to reducethe azide group. In some embodiments, the reaction is carried out at atemperature from about 35° C. to about 75° C. (e.g., at about 55° C.).The resultant NH₂-containing intermediate is reacted with a protectinggroup (e.g., Boc anhydride) to yield (11).

Step 9: Intermediate (11) is reacted with bispinacolatodiborane toobtain (12). In some embodiments, the reaction is carried out in thepresence of a catalyst (e.g., PdCl₂(dppf).CH₂Cl₂). In some embodiments,the reaction is carried out in a solvent (e.g., dimethyl sulfoxide(DMSO)). In some embodiments, the reaction is carried out in thepresence of a base (e.g., potassium acetate).

Step 10: Intermediate (12) is reacted with 5-iodocytosine to yield thefree amine intermediate. In some embodiments, the reaction is carriedout in presence of a catalyst and a ligand (e.g., copper acetatemonohydrate and tetramethylehtylenediamine). The free amine intermediateis reacted with a protecting group (e.g., benzoic anhydride) to yield(13).

Step 11: Intermediate (13) is reacted with (14) to yield a protectedintermediate. In some embodiments, the reaction is carried out underSonogashira coupling conditions. In some embodiments, the reaction iscarried in the presence of catalyst (e.g., Pd(PPh₃)₄ and CuI) and aligand (e.g., N—N-diisopropylethylamine). The protecyted intermediate ishydrolyzed in the presence of an alcohol (e.g., methanol) to yield (15).

Step 12: Intermediate (15) is reacted with an acid (e.g., HCl) to yield(16). In some embodiments, the reaction is carried out in the presenceof Charcoal-siliathiol.

Step 13: Intermediate (16) is reacted with ethoxyimine (18) to aprotected intermediate. In some embodiments, the reaction is carried outin the presence of diisopropylethyl amine (DIPEA). The resultantCbz-protected intermediate was reacted with an acid (e.g., HBr or HBrsolution in acetic acid) to yield (17).

An analogous scheme may be used starting with 2′, shown below, insteadof 2, to obtain a compound of Formula (I) or Formula (II) wherein W isN.

Referring to Scheme 2:

Substituted acetonitrile (19) is reacted with ethanol in the presence ofan acid (e.g., HCl) to obtain (18). In some embodiments, the reaction iscarried out 0° C. In some embodiments, the reaction is carried out in 4NHCl solution in organic solvent (e.g., 1, 4-dioxane).

Referring to Scheme 3:

Step 1: Alcohol (30) is reacted with an azide-containing reagent toobtain an azide (31). In some embodiments, the azide-containing reagentis NaN₃. In some embodiments, the alcohol (30) is reacted withmethanesulfonyl chloride prior to reaction with NaN₃.

Step 2: The azide (31) is reacted with triphenylphosphine to reduce theazide group and obtain the free amine-containing intermediate. Thefree-amine containing intermediate is reacted with a protecting group(e.g., Cbz-Cl) to yield (32).

Step 3: Alkene (32) is reacted with a boron reagent (e.g., 9-BBN) toobtain a boron intermediate which is further reacted with bromobenzene(33) to yield (34). In some embodiments, the reaction in carried out inthe presence of a catalyst (e.g., Pd(PPh₃)₄). In some embodiments, thereaction is carried out at a temperature from about 40° C. to about 80°C. (e.g., about 60° C.).

Step 4: bromobenzene (34) is reacted with an acetylene reagent (e.g.,TMS-acetylene) to yield (14). In some embodiments, the reaction iscarried out in the presence of a base (e.g., K₂CO₃).

In some embodiments, intermediate 14 can be prepared using methods andprocedures analogous to those described in PCT/US2014/054869 and U.S.provisional application 61/875,643, the disclosures of which areincorporated herein by reference in their entireties.

The specific approaches and compounds shown in the schemes above are notintended to be limiting. The chemical structures in the schemes hereindepict variables that are hereby defined commensurately with chemicalgroup definitions (moieties, atoms, etc.) of the corresponding positionin the compound formulae herein, whether identified by the same variablename (i.e., R₁, R₂, R₃, etc.) or not. The suitability of a chemicalgroup in a compound structure for use in the synthesis of anothercompound is within the knowledge of one of ordinary skill in the art.

Additional methods of synthesizing compounds of the formulae herein andtheir synthetic precursors, including those within routes not explicitlyshown in schemes herein, are within the means of chemists of ordinaryskill in the art. Synthetic chemistry transformations and protectinggroup methodologies (protection and deprotection) useful in synthesizingthe applicable compounds are known in the art and include, for example,those described in Larock R, Comprehensive Organic Transformations, VCHPublishers (1989); Fieser L et al., Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and Paquette L, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995) and subsequent editions thereof.

4. Characterization of Compounds of the Disclosure

Compounds designed, selected and/or optimized by methods describedabove, once produced, can be characterized using a variety of assaysknown to those skilled in the art to determine whether the compoundshave biological activity. For example, the molecules can becharacterized by conventional assays, including but not limited to thoseassays described below, to determine whether they have a predictedactivity, binding activity and/or binding specificity.

Furthermore, high-throughput screening can be used to speed up analysisusing such assays. As a result, it can be possible to rapidly screen themolecules disclosed herein for activity, for example, as anti-cancer,anti-bacterial, anti-fungal, anti-parasitic or anti-viral agents. Also,it can be possible to assay how the compounds interact with a ribosomeor ribosomal subunit and/or are effective as modulators (for example,inhibitors) of protein synthesis using techniques known in the art.General methodologies for performing high-throughput screening aredescribed, for example, in Devlin (1998) High Throughput Screening,Marcel Dekker; and U.S. Pat. No. 5,763,263. High-throughput assays canuse one or more different assay techniques including, but not limitedto, those described below.

(1) Surface Binding Studies. A variety of binding assays can be usefulin screening new molecules for their binding activity. One approachincludes surface plasmon resonance (SPR) that can be used to evaluatethe binding properties of molecules of interest with respect to aribosome, ribosomal subunit or a fragment thereof.

SPR methodologies measure the interaction between two or moremacromolecules in real-time through the generation of aquantum-mechanical surface plasmon. One device, (BIAcore Biosensor® fromPharmacia Biosensor, Piscataway, N.J.) provides a focused beam ofpolychromatic light to the interface between a gold film (provided as adisposable biosensor “chip”) and a buffer compartment that can beregulated by the user. A 100 nm thick “hydrogel” composed ofcarboxylated dextran that provides a matrix for the covalentimmobilization of analytes of interest is attached to the gold film.When the focused light interacts with the free electron cloud of thegold film, plasmon resonance is enhanced. The resulting reflected lightis spectrally depleted in wavelengths that optimally evolved theresonance. By separating the reflected polychromatic light into itscomponent wavelengths (by means of a prism), and determining thefrequencies that are depleted, the BIAcore establishes an opticalinterface which accurately reports the behavior of the generated surfaceplasmon resonance. When designed as above, the plasmon resonance (andthus the depletion spectrum) is sensitive to mass in the evanescentfield (which corresponds roughly to the thickness of the hydrogel). Ifone component of an interacting pair is immobilized to the hydrogel, andthe interacting partner is provided through the buffer compartment, theinteraction between the two components can be measured in real timebased on the accumulation of mass in the evanescent field and itscorresponding effects of the plasmon resonance as measured by thedepletion spectrum. This system permits rapid and sensitive real-timemeasurement of the molecular interactions without the need to labeleither component.

(2) Fluorescence Polarization. Fluorescence polarization (FP) is ameasurement technique that can readily be applied to protein-protein,protein-ligand, or RNA-ligand interactions in order to derive IC_(50s)and Kds of the association reaction between two molecules. In thistechnique one of the molecules of interest is conjugated with afluorophore. This is generally the smaller molecule in the system (inthis case, the compound of interest). The sample mixture, containingboth the ligand-probe conjugate and the ribosome, ribosomal subunit orfragment thereof, is excited with vertically polarized light. Light isabsorbed by the probe fluorophores, and re-emitted a short time later.The degree of polarization of the emitted light is measured.Polarization of the emitted light is dependent on several factors, butmost importantly on viscosity of the solution and on the apparentmolecular weight of the fluorophore. With proper controls, changes inthe degree of polarization of the emitted light depends only on changesin the apparent molecular weight of the fluorophore, which in-turndepends on whether the probe-ligand conjugate is free in solution, or isbound to a receptor. Binding assays based on FP have a number ofimportant advantages, including the measurement of IC_(50s) and Kdsunder true homogenous equilibrium conditions, speed of analysis andamenity to automation, and ability to screen in cloudy suspensions andcolored solutions.

(3) Protein Synthesis. It is contemplated that, in addition tocharacterization by the foregoing biochemical assays, the compound ofinterest can also be characterized as a modulator (for example, aninhibitor of protein synthesis) of the functional activity of theribosome or ribosomal subunit.

Furthermore, more specific protein synthesis inhibition assays can beperformed by administering the compound to a whole organism, tissue,organ, organelle, cell, a cellular or subcellular extract, or a purifiedribosome preparation and observing its pharmacological and inhibitoryproperties by determining, for example, its inhibition constant (IC₅₀)for inhibiting protein synthesis. Incorporation of ³H leucine or ³⁵Smethionine, or similar experiments can be performed to investigateprotein synthesis activity. A change in the amount or the rate ofprotein synthesis in the cell in the presence of a molecule of interestindicates that the molecule is a modulator of protein synthesis. Adecrease in the rate or the amount of protein synthesis indicates thatthe molecule is an inhibitor of protein synthesis.

(4) Antimicrobial assay and other evaluation. Furthermore, the compoundscan be assayed for anti-proliferative or anti-infective properties on acellular level. For example, where the target organism is amicroorganism, the activity of compounds of interest can be assayed bygrowing the microorganisms of interest in media either containing orlacking the compound. Growth inhibition can be indicative that themolecule can be acting as a protein synthesis inhibitor. Morespecifically, the activity of the compounds of interest againstbacterial pathogens can be demonstrated by the ability of the compoundto inhibit growth of defined strains of human pathogens. For thispurpose, a panel of bacterial strains can be assembled to include avariety of target pathogenic species, some containing resistancemechanisms that have been characterized. Use of such a panel oforganisms permits the determination of structure-activity relationshipsnot only in regards to potency and spectrum, but also with a view toobviating resistance mechanisms.

(5) The translation-only assay for ribosomal protein production usespurified 70S ribosomes, corresponding S100 extracts containing thebiological molecules necessary to support protein translation, and mRNAencoding firefly luciferase or another protein reporter. The resultingluminescence signal is proportional to protein translation and isdetermined by a luminescence assay plate reader (i.e. Victor2VMultilabel Reader). This assay is performed with varying concentrationsof potential translation inhibitors in the assay. The resulting data areused to calculate IC50 values of inhibition for the compounds usingappropriate software (i.e. MDL Assay Explorer with a one-sitecompetition model of binding).

The in vitro activity of the compounds of the present disclosure can bedetermined. Antimicrobial testing is typically performed to determinethe minimum inhibitory concentration (MIC). Minimum inhibitoryconcentrations (MICs) are determined by the microdilution method in afinal volume of 100 μl according to protocols outlined by The Clinicaland Laboratory Standards Institute (CLSI). Performance standards forreference strains are assessed within the same experimental design tomaintain quality control. See, for example, Clinical LaboratoryStandards Institute: Methods for dilution antimicrobial susceptibilitytests for bacteria that grow aerobically M7-A8. Approved Standard-EighthEdition. Wayne, Pa.: CLSI; December 2008; and Clinical LaboratoryStandards Institute: Performance Standards for AntimicrobialSusceptibility Testing M100-S20; Approved Standard-Twentieth Edition.Wayne, Pa.: CLSI; June 2010.

For example, an agar-dilution MIC assay could be run using the followingprotocol. Pure cultures of isolates to be tested are grown on ChocolateAgar at 35′C to 36.5° C. in a CO₂ enriched (5%) atmosphere for 16-18hours. Using a cotton applicator or a bacteriologic loop, isolatedcolonies (or cells from less dense areas of growth on the plate) aresuspended in 5 mL saline. The density of the suspension is then adjustedto contain 10⁸ colony forming units (CFU)/ml by comparison with a 0.5McFarland BaSO₄ turbidity standard. This suspension is then diluted in1:10 in MH broth to give 10⁷ CFU/ml. Using a multichannel pipettor,0.002 mL spots of the bacterial suspension is dispensed onto the surfaceof the medium, i.e., 104 CFU. Each plate of the set of antibioticcontaining media plus a plate of Chocolate Agar or GCS medium (as acontrol to determine that all isolates grew) is inoculated. Theinoculated plates are air-dried at room temperature for approximately 15minutes. The plates are then inverted and incubated at 35° C. to 36.5°C. in a CO₂-enriched (5%) atmosphere for 24 hours. The plates are thenexamined for growth.

Another in vitro assay that can be performed is a time-kill kineticassay. Using this assay, bactericidal activity can be determined bytime-kill methodology as described by Clinical Laboratory StandardsInstitute. For example, the compounds to be tested are added to testflasks at concentrations of 2×-32× the MIC (determined, for example,using the assays described herein). Once dissolved, compounds arediluted in Giolitti Cantoni (GC) broth to a volume of 1 mL at the 25×desired final concentration; a flask containing 1 mL of GC broth withoutcompound is prepared as a growth control. A 0.5 McFarland equivalent isprepared for the test organism, diluted 1.200 in pre-warmed GC broth,and incubated in 5% CO₂-enriched atmosphere at 35° C. for 30 minutesprior to exposure to the test compound. After the 30-minutepre-incubation, 24 mL is removed and added to each test flask for afinal volume of 25 mL. A sample is removed from the growth controlflask, diluted in Phosphate Buffered Saline (PBS) and plated onChocolate Agar (CA) to confirm an inoculum of approximately 5×10⁵CFU/mL. Samples are then removed from all flasks at 1, 2, 4, 6, 8, and24 hours, diluted in PBS and plated on CA to determine the number ofviable cells in each flask. Plate counts are incubated at 35° C. in 5%CO₂-enriched atmosphere for 48 hours and colonies are counted. Platecounts are then graphed.

The antimicrobial and other drug properties of the compounds can furtherbe evaluated in various in vivo mammalian assays, such as a mouse or ratperitonitis infectious models, skin and soft tissue models (oftenreferred to as the thigh model), or a mouse pneumonia model. There aresepticemia or organ infection models known to those skilled in the art.These efficacy models can be used as part of the evaluation process andcan be used as a guide of potential efficacy in humans. Endpoints canvary from reduction in bacterial burden to lethality. For the latterendpoint, results are often expressed as a PD₅₀ value, or the dose ofdrug that protects 50% of the animals from mortality.

To further assess a compound's drug-like properties, measurements ofinhibition of cytochrome P450 enzymes and phase II metabolizing enzymeactivity can also be measured either using recombinant human enzymesystems or more complex systems like human liver microsomes. Further,compounds can be assessed as substrates of these metabolic enzymeactivities as well. These activities are useful in determining thepotential of a compound to cause drug-drug interactions or generatemetabolites that retain or have no useful antimicrobial activity.

To get an estimate of the potential of the compound to be orallybioavailable, one can also perform solubility and Caco-2 assays. Thelatter is a cell line from human epithelium that allows measurement ofdrug uptake and passage through a Caco-2 cell monolayer often growingwithin wells of a 24-well microtiter plate equipped with a 1 micronmembrane. Free drug concentrations can be measured on the basolateralside of the monolayer, assessing the amount of drug that can passthrough the intestinal monolayer. Appropriate controls to ensuremonolayer integrity and tightness of gap junctions are needed. Usingthis same system one can get an estimate of P-glycoprotein mediatedefflux. P-glycoprotein is a pump that localizes to the apical membraneof cells, forming polarized monolayers. This pump can abrogate theactive or passive uptake across the Caco-2 cell membrane, resulting inless drug passing through the intestinal epithelial layer. These resultsare often done in conjunction with solubility measurements and both ofthese factors are known to contribute to oral bioavailability inmammals. Measurements of oral bioavailability in animals and ultimatelyin man using traditional pharmacokinetic experiments will determine theabsolute oral bioavailability.

Experimental results can also be used to build models that help predictphysical-chemical parameters that contribute to drug-like properties.When such a model is verified, experimental methodology can be reduced,with increased reliance on the model predictability.

(5) Animal Pharmacology and Toxicology. The compounds of the presentdisclosure can be evaluated for efficacy in well-known animal models.The following table provides representative animal models for variousinfection indications.

Target Infection Indication Animal Model of Efficacy HAP/VAP Efficacy inmouse and/or rat pneumoniae model vs. respiratory tract infectionpathogens of interest (Streptococcus pneumoniae, including multi-drugresistant Streptococcus pneumoniae, H. influenzae, methicillin resistantStaphylococcus aureus (MRSA), and Pseudomonas. aeruginosa) cSSSIEfficacy tn mouse model against pathogens of interest (MRSA. K.pneumoniae) Sepsis Efficacy in mouse peritonitis model vs. pathogens ofinterest (E. coli, K. pneumoniae, E. Jaecalis, MRSA) cUTI Efficacy inmouse model against E. coli, K. pneumoniae and/or MRSA) Febrile Efficacyin mouse peritonitis model against neutropenia A. aureus, S.epidermidis, S. pneumoniae, S. pyogenes, P. aeruginosaAnimal Model for Complicated Skin and Skin Structure Infections (cSSSI):Murine Skin and Soft Tissue Infection Model of Klebsiella pneumoniae1705966 in Thighs of Neutropenic Female CD-1 Mice

This model is useful to assess the efficacy of compounds of the presentdisclosure in a Klebsiella pneumoniae 1705966 neutropenic mouse thighinfection model using female ICR (CD-1) mice.

Study Design:

Species: Female ICR (CD-1) Mice, 8 to 9 weeks old, weighting 25-29 g.

Inoculum: Klebsiella pneumoniae 17059663 was streaked from frozen stockonto Blood agar (Tryptic Soy Agar+5% Sheep Blood), BD, #221261) andincubated overnight at 35° C. After overnight incubation, enoughbacteria (approx. 1 full loop) to measure OD₆₂₅=0.990 was transferredfrom plate and diluted into 10 ml pre-warmed Mueller-Hinton broth. Thisculture was further diluted 1:1000 into pre-warmed MH broth and grownfor approximately 2 hours at 35° C. with shaking. Each mouse was given0.1 mL of 1:1000 dilution culture injected into both caudal thighmuscles under isoflurane inhalation anesthesia.

Final O.D Dilution Initial O.D. (after ~2 hr. incubation) 1:10 0.1350.424 1:100 0.014 0.215 1:1000 0.001 0.035Neutropenia is induced by intraperitoneal (I.P.) administration ofCyclophosphamide monohydrate on Day −4 (150 mg/kg) and Day −1 (100mg/kg).

Vehicle: 0.9% sodium chloride

Dosing: Each mouse in the treated groups was given the appropriate doseof the compound to be tested in a volume of 0.2 ml, 2 and 8 hrs. postbacterial inoculation.

Time Points:

Controls: 0, 2, 6, and 24 hrs.

Treated: 24 hrs.

Sampling: 2 or 3 mice/time point were euthanized via CO₂, and theircaudal thigh muscles excised and homogenized. The thigh muscles wereplaced in 5 ml sterile PBS in Stomacher Filter bag and homogenized withMicroBiomaster80 (Brinkmann) for 60 seconds, normal setting and 1:10dilutions were made per standard protocol in a 96-well plate. Aliquotsof 25 ul for each dilution, as well as the homogenate, were plated onblood agar plates and incubated at 35° C. to determine the CFU/mL overthe time course. After overnight incubation, colonies were counted.

Animal Model for Sepsis:

Murine peritonitis model (E. coli, K. pneumoniae, E. faecalis, MRSA)

This model is used to evaluate the effect of subcutaneous (SC) treatmentwith compounds of the present disclosure on growth of Escherichia coliATCC 25922 in a mouse peritonitis model using female Swiss Webster mice.

Controls:

Negative: Inoculum only

Inoculum Vehicle Intraperitoneal

Positive: Ciprofloxacin

Study Design:

Species: Female Swiss Webster Mice

Inoculation: Escherichia coli ATCC 25922 is made by adding 1 ml (4/6/07)stock to 9 ml 0.25% Brewer's Yeast to make (1:10), then 1 ml of the(1:10) will be added to 9 ml 0.25% Brewer's Yeast to make (1:100), then1 ml of the (1:100) will be added to 9 ml 0.25% Brewer's Yeast to make(1:1000), then 2.5 ml of the (1:1000) will be added to 122.5 ml 0.25%Brewer's Yeast to make (1:50,000), 1 ml/mouse will be inoculatedintraperitoneally (IP).

Route of Administration: SC

Dosing: Vehicle for compounds of the present disclosure: Saline or 50 mMSodium phosphate buffer in 10% Captisol in water, pH=7.2.

Dose Administration: Q3H×3 beginning at 30 min post bacterialinoculation

Study Duration: 24 hrs. 0.25% Brewer's Yeast Extract (BYE): Dilute 2%prepared on Nov. 12, 2009 (Lot. 2158K, MP Biomedicals) 25 ml 2%+175 ml1×PBS.

Outcome Measures: Colony Forming Unit's from peritoneal wash and spleenhomogenate and drug levels from wash, spleen homogenate, and plasma.

Blood is collected via cardiac puncture while mouse is under CO₂narcosis. The whole blood sample is placed in heparinized eppendorftubes and kept on wet ice until centrifuged (4 min @ 14,000 rpm). Plasmais transferred to 96 deep-well block on dry ice and stored at −20° C.Immediately following blood collection, 2 ml of sterile PBS (phosphatebuffered saline) was injected into the peritoneal cavity with a 25 Gneedle. The abdomen was gently massaged, and a small incision was madeto allow access to the peritoneal cavity. The peritoneal wash fluid wascollected using sterile technique, serially diluted 1:10, plated onblood agar plates, and incubated overnight at 35° C.

Spleens were harvested and placed in 1 ml sterile PBS in Stomacher bagand homogenized with MicroBiomaster80 (Brinkmann) for 60 seconds, normalsetting and 1:10 dilutions were made. 25 μl of each dilution, as well asthe homogenate, was plated on blood agar plates and incubated at 35° C.to determine the CFU/mL over the time course. After overnightincubation, colonies were counted.

Other Animal Models

Similarly, other animal infection models can be used for hospitalacquired pneumonia (HAP)/ventilator acquired pneumonia (VAP),complicated urinary tract infections (cUTI), and febrile neutropenia.

5. Formulation and Administration

The compositions and methods of the present disclosure can be practicedby delivering the compounds of the present disclosure using a means fordelivery e.g., any suitable carrier. The dose of active compound, modeof administration and use of suitable carrier will depend upon theintended patient or subject and the targeted microorganism, e.g., thetarget bacterial organism. The formulations, both for human medical useand veterinary use, of compounds according to the present disclosuretypically include such compounds in association with a pharmaceuticallyacceptable carrier.

The carrier(s) should be “acceptable” in the sense of being compatiblewith compounds of the present disclosure and not deleterious to therecipient. Pharmaceutically acceptable carriers, in this regard, areintended to include any and all solvents, dispersion media, coatings,absorption delaying agents, and the like, compatible with pharmaceuticaladministration. Supplementary active compounds (identified or designedaccording to the disclosure and/or known in the art) also can beincorporated into the compositions. In some embodiments, someformulations are prepared by bringing the compound into association witha liquid carrier or a finely divided solid carrier or both, and then, ifnecessary, shaping the product into the desired formulation.

A pharmaceutical composition of the disclosure should be formulated tobe compatible with its intended route of administration. Solutions orsuspensions can include the following components: a sterile diluent suchas water, saline solution, fixed oils, polyethylene glycols, glycerine,propylene glycol or other synthetic solvents; antibacterial agents suchas benzyl alcohol or methyl parabens; antioxidants such as ascorbic acidor sodium bisulfite; chelating agents such as ethylenediaminetetraaceticacid; buffers such as acetates, citrates or phosphates and agents forthe adjustment of tonicity such as sodium chloride or dextrose. The pHcan be adjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide.

Formulations for parenteral administration can also include glycocholatefor buccal administration, methoxysalicylate for rectal administration,or citric acid for vaginal administration. The parenteral preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic. Suppositories for rectal administration alsocan be prepared by mixing the drug with a non-irritating excipient suchas cocoa butter, other glycerides, or other compositions which are solidat room temperature and liquid at body temperatures. Formulations alsocan include, for example, polyalkylene glycols such as polyethyleneglycol, oils of vegetable origin, and hydrogenated naphthalenes.Formulations for direct administration can include glycerol and othercompositions of high viscosity. Other potentially useful parenteralcarriers for these drugs include ethylene-vinyl acetate copolymerparticles, osmotic pumps, implantable infusion systems, and liposomes.Formulations for inhalation administration can contain as excipients,for example, lactose, or can be aqueous solutions containing, forexample, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate,or oily solutions for administration in the form of nasal drops, or as agel to be applied intranasally. Retention enemas also can be used forrectal delivery.

Formulations of the present disclosure suitable for oral administrationcan be in the form of: discrete units such as capsules, gelatincapsules, sachets, tablets, troches, or lozenges, each containing apredetermined amount of the drug; a powder or granular composition; asolution or a suspension in an aqueous liquid or non-aqueous liquid; oran oil-in-water emulsion or a water-in-oil emulsion. The drug can alsobe administered in the form of a bolus, electuary or paste. A tablet canbe made by compressing or molding the drug optionally with one or moreaccessory ingredients. Compressed tablets can be prepared bycompressing, in a suitable machine, the drug in a free-flowing form suchas a powder or granules, optionally mixed by a binder, lubricant, inertdiluent, surface active or dispersing agent. Molded tablets can be madeby molding, in a suitable machine, a mixture of the powdered drug andsuitable carrier moistened with an inert liquid diluent.

Oral compositions generally include an inert diluent or an ediblecarrier. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients. Oral compositions preparedusing a fluid carrier for use as a mouthwash include the compound in thefluid carrier and are applied orally and swished and expectorated orswallowed. Pharmaceutically compatible binding agents, and/or adjuvantmaterials can be included as part of the composition. The tablets,pills, capsules, troches and the like can contain any of the followingingredients, or compounds of a similar nature: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose; a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate orSterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). Itshould be stable under the conditions of manufacture and storage andshould be preserved against the contaminating action of microorganismssuch as bacteria and fungi. The carrier can be a solvent or dispersionmedium containing, for example, water, ethanol, polyol (for example,glycerol, propylene glycol, and liquid polyethylene glycol), andsuitable mixtures thereof. The proper fluidity can be maintained, forexample, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersion and by the use ofsurfactants. In many cases, it will be preferable to include isotonicagents, for example, sugars, polyalcohols such as mannitol, sorbitol,and sodium chloride in the composition. Prolonged absorption of theinjectable compositions can be brought about by including in thecomposition an agent which delays absorption, for example, aluminummonostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed byfilter sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle which containsa basic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, methods of preparation include vacuumdrying and freeze-drying which yields a powder of the active ingredientplus any additional desired ingredient from a previouslysterile-filtered solution thereof.

Formulations suitable for intra-articular administration can be in theform of a sterile aqueous preparation of the drug that can be inmicrocrystalline form, for example, in the form of an aqueousmicrocrystalline suspension. Liposomal formulations or biodegradablepolymer systems can also be used to present the drug for bothintra-articular and ophthalmic administration.

Formulations suitable for topical administration, including eyetreatment, include liquid or semi-liquid preparations such as liniments,lotions, gels, applicants, oil-in-water or water-in-oil emulsions suchas creams, ointments or pastes; or solutions or suspensions such asdrops. Formulations for topical administration to the skin surface canbe prepared by dispersing the drug with a dermatologically acceptablecarrier such as a lotion, cream, ointment or soap. Useful are carrierscapable of forming a film or layer over the skin to localize applicationand inhibit removal. For topical administration to internal tissuesurfaces, the agent can be dispersed in a liquid tissue adhesive orother substance known to enhance adsorption to a tissue surface. Forexample, hydroxypropylcellulose or fibrinogen/thrombin solutions can beused to advantage. Alternatively, tissue-coating solutions, such aspectin-containing formulations can be used.

For inhalation treatments, inhalation of powder (self-propelling orspray formulations) dispensed with a spray can, a nebulizer, or anatomizer can be used. Such formulations can be in the form of a finepowder for pulmonary administration from a powder inhalation device orself-propelling powder-dispensing formulations. In the case ofself-propelling solution and spray formulations, the effect can beachieved either by choice of a valve having the desired spraycharacteristics (i.e., being capable of producing a spray having thedesired particle size) or by incorporating the active ingredient as asuspended powder in controlled particle size. For administration byinhalation, the compounds also can be delivered in the form of anaerosol spray from pressured container or dispenser which contains asuitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

Systemic administration also can be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants include, for example, for transmucosal administration,detergents and bile salts. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active compounds typically areformulated into ointments, salves, gels, or creams.

The active compounds can be prepared with carriers that will protect thecompound against rapid elimination from the body, such as a controlledrelease formulation, including implants and microencapsulated deliverysystems. Biodegradable, biocompatible polymers can be used, such asethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen,polyorthoesters, and polylactic acid. Liposomal suspensions can also beused as pharmaceutically acceptable carriers.

Oral or parenteral compositions can be formulated in dosage unit formfor ease of administration and uniformity of dosage. Dosage unit formrefers to physically discrete units suited as unitary dosages for thesubject to be treated; each unit containing a predetermined quantity ofactive compound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the disclosure are dictated by and directlydependent on the unique characteristics of the active compound and thetherapeutic effect to be achieved, and the limitations inherent in theart of compounding such an active compound for the treatment ofindividuals. Furthermore, administration can be by periodic injectionsof a bolus, or can be made more continuous by intravenous, intramuscularor intraperitoneal administration from an external reservoir (e.g., anintravenous bag).

Where adhesion to a tissue surface is desired the composition caninclude the drug dispersed in a fibrinogen-thrombin composition or otherbioadhesive. The compound then can be painted, sprayed or otherwiseapplied to the desired tissue surface. Alternatively, the drugs can beformulated for parenteral or oral administration to humans or othermammals, for example, in effective amounts, e.g., amounts that provideappropriate concentrations of the drug to target tissue for a timesufficient to induce the desired effect.

Where the active compound is to be used as part of a transplantprocedure, it can be provided to the living tissue or organ to betransplanted prior to removal of tissue or organ from the donor. Thecompound can be provided to the donor host. Alternatively or, inaddition, once removed from the donor, the organ or living tissue can beplaced in a preservation solution containing the active compound. In allcases, the active compound can be administered directly to the desiredtissue, as by injection to the tissue, or it can be providedsystemically, either by oral or parenteral administration, using any ofthe methods and formulations disclosed herein. Where the drug comprisespart of a tissue or organ preservation solution, any commerciallyavailable preservation solution can be used to advantage. For example,useful solutions known in the art include Collins solution, Wisconsinsolution, Belzer solution, Eurocollins solution and lactated Ringer'ssolution.

Generally, an effective amount of dosage of active compound will be inthe range of from about 0.1 to about 100 mg/kg of body weight/day, morepreferably from about 1.0 to about 50 mg/kg of body weight/day. Theamount administered will also likely depend on such variables as thetype of surgery or invasive medical procedure, the overall health statusof the patient, the relative biological efficacy of the compounddelivered, the formulation of the drug, the presence and types ofexcipients in the formulation, and the route of administration. Also, itis to be understood that the initial dosage administered can beincreased beyond the above upper level in order to rapidly achieve thedesired blood-level or tissue level, or the initial dosage can besmaller than the optimum.

Nonlimiting doses of active compound comprise from about 0.1 to about1500 mg per dose.

As is understood by one of ordinary skill in the art, generally, whendosages are described for a pharmaceutical active, the dosage is givenon the basis of the parent or active moiety. Therefore, if a salt,hydrate, or another form of the parent or active moiety is used, acorresponding adjustment in the weight of the compound is made, althoughthe dose is still referred to on the basis of the parent or activemoiety delivered. As a nonlimiting example, if the parent or activemoiety of interest is a monocarboxylic acid having a molecular weight of250, and if the monosodium salt of the acid is desired to be deliveredto be delivered at the same dosage, then an adjustment is maderecognizing that the monosodium salt would have a molecular weight ofapproximately 272 (i.e., minus 1H or 1.008 atomic mass units and plus 1Na or 22.99 atomic mass units). Therefore, a 250 mg dosage of the parentor active compound would correspond to about 272 mg of the monosodiumsalt, which would also deliver 250 mg of the parent or active compound.Said another way, about 272 mg of the monosodium salt would beequivalent to a 250 mg dosage of the parent or active compound.

Formulation Examples IA. Formulation for Intravenous Administration

Ingredients Amount Antimicrobial Compound 0.1-1500 total mg of thepresent disclosure Dextrose, USP 50 mg/ml Sodium citrate, USP 1.60-1.75mg/ml Citric Acid, USP 0.80-0.90 mg/ml Water, USP q.s

This formulation for intravenous administration is formulated by heatingwater for injection to about 60° C. Next the sodium citrate, citric acidand dextrose are added and stirred until dissolved. A solution oraqueous slurry of the antimicrobial compound is added to the previousmixture and stirred until dissolved. The mixture is cooled to 25° C.with stirring. The pH is measured and adjusted if necessary. Lastly themixture is brought to the desired volume, if necessary, with water forinjection. The mixture is filtered, filled into the desired container(vial, syringe, infusion container, etc.), over wrapped and terminallymoist heat sterilized.

This formulation is useful for intravenous administration, either bolusor infusion, to a patient for treating, preventing, reducing the riskof, or delaying the onset of infection.

IB. Formulation for Intravenous Administration

This formulation for intravenous administration utilizes 6.5 nM tartaricacid buffer in 5% Dextrose, and has a pH of 4.4. This formulation isuseful for intravenous administration, either bolus or infusion, to apatient for treating, preventing, reducing the risk of, or delaying theonset of infection.

II. Lyophilisate for Reconstitution

Alternatively, the antimicrobial compound can be provided as alyophilisate which can be reconstituted before intravenous orintramuscular administration.

Ingredient mg per injection vial Antimicrobial Compound 01-1500 of thepresent disclosure Cyclodextrin 1500

Reconstitution solution for a volume to be administered of 50 ml(infusion): 5% aqueous glucose solution.

Reconstitution solution for a volume to be administered of 15 ml(bolus): 3.3% aqueous glucose solution.

The foregoing lyophilisate is useful for reconstitution and intravenousadministration, either bolus or infusion, to a patient for treating,preventing, reducing the risk of, or delaying the onset of infection.

III. Lyophilisate for Reconstitution

Ingredient mg per injection vial Antimicrobial Compound 0.1-1500 of thepresent disclosure soya lecithin 2250 Sodium cholate 1500

Reconstitution solution for a volume to be administered of 50 ml(infusion): 4% aqueous glucose solution.

Reconstitution solution for a volume to be administered of 15 ml(bolus): 2% aqueous glucose solution

The foregoing lyophilisate is useful for reconstitution and intravenousadministration, either bolus or infusion, to a patient for treating,preventing, reducing the risk of, or delaying the onset of infection.

IV. Lyophilisate for Reconstitution

Ingredient mg per injection vial Antimicrobial Compound 0.1-1500 of thepresent disclosure soya lecithin 900 Sodium glycocholate 540

Reconstitution solution for a volume to be administered of 15 ml(bolus): 3.3% aqueous glucose solution.

The foregoing lyophilisate is useful for reconstitution and intravenousadministration, either bolus or infusion, to a patient for treating,preventing, reducing the risk of, or delaying the onset of infection.

V. Tablet for Oral Administration

Ingredients Per Tablet Per 4000 Tablets Antimicrobial Compound 0.1-1500mg 0.4-6000 g of the present disclosure 110.45 mg 441.8 g AnhydrousLactose, NF Microcrystalline 80.0 mg 320.0 g Cellulose NF MagnesiumStearate 1.00 mg 4.0 g Impalpable Powder NF Croscarmellose Sodium 2.00mg 8.0 g NF Type A

The antimicrobial compound (any of the compounds equivalent to thedesired delivery strength, e.g., 50 to 1500 mg per tablet) is premixedwith ⅓ of the microcrystalline cellulose NF and ½ of the anhydrouslactose NF in a ribbon blender for 5 minutes at 20 RPM. To the premix isadded the remaining ⅔ of the microcrystalline cellulose NF and theremaining ½ of the anhydrous lactose NF. This is blended for 10 minutesat 20 RPM. Croscarmellose sodium is added to the blended powders andmixed for 5 minutes at 20 RPM. Finally the magnesium stearate is addedto the mixture by passing through a 90 mesh screen and blended for anadditional 5 minutes at 20 RPM. The lubricated mixture is compressed toprovide tablets of 500 mg active ingredient.

These tablets are useful for oral administration to a patient fortreating, prevention, reducing the risk of, or delaying the onset ofinfection.

6. Examples

Nuclear magnetic resonance (NMR) spectra were obtained on a BrukerAvance 300 or Avance 500 spectrometer, or in some cases a GE-Nicolet 300spectrometer. Common reaction solvents were either high performanceliquid chromatography (HPLC) grade or American Chemical Society (ACS)grade, and anhydrous as obtained from the manufacturer unless otherwisenoted. “Chromatography” or “purified by silica gel” refers to flashcolumn chromatography using silica gel (EM Merck, Silica Gel 60, 230-400mesh) unless otherwise noted.

The compounds or tautomers thereof, or pharmaceutically acceptable saltsof said compounds or tautomers of the present disclosure can be preparedusing known chemical transformations adapted to the particular situationat hand.

Some of the abbreviations used in the following experimental details ofthe synthesis of the examples are defined below: h or hr=hour(s);min=minute(s); mol=mole(s); mmol=millimole(s); M=molar; μM=micromolar;g=gram(s); μg=microgram(s); rt=room temperature; L=liter(s);mL=milliliter(s); Et₂O=diethyl ether, THF=tetrahydrofuran; DMSO=dimethylsulfoxide; EtOAc=ethyl acetate; Et₃N=triethylamine; i-Pr₂NEt orDIPEA=diisopropylethylamine; CH₂Cl₂=methylene chloride;CHCl₃=chloroform: CDCl₃=deuterated chloroform; CCl₄=carbontetrachloride; MeOH=methanol; CD₃OD=deuterated methanol; EtOH=ethanol;DMF=dimethylformamide; BOC=t-butoxycarbonyl; CBZ=benzyloxycarbonyl;TBS=t-butyldimethylsilyl; TBSCl=t-butyldimethylsilyl chloride;TFA=trifluoroacetic acid; DBU=diazabicycloundecene;TBDPSCl=t-butyldiphenylchlorosilane; Hunig'sBase=N,N-diisopropylethylamine; DMAP=4-dimethylaminopyridine; CuI=copper(I) iodide; MsCl=methanesulfonyl chloride; NaN₃=sodium azide;Na₂SO₄=sodium sulfate; NaHCO₃=sodium bicarbonate; NaOH=sodium hydroxide;MgSO₄=magnesium sulfate; K₂CO₃=potassium carbonate; KOH=potassiumhydroxide; NH₄OH=ammonium hydroxide; NH₄Cl=ammonium chloride;SiO₂=silica; Pd—C=palladium on carbon;Pd(dppf)Cl₂=dichloro[1,1′-bis(diphenylphosphino)ferrocene] palladium(TI).

Exemplary compounds synthesized in accordance with the disclosure arelisted in Table 1, Table 1a, or Table 1b. A bolded or dashed bond isshown to indicate a particular stereochemistry at a chiral center,whereas a wavy bond indicates that the substituent can be in eitherorientation or that the compound is a mixture thereof.

The compounds of the present disclosure can be prepared, formulated, anddelivered as salts. For convenience, the compounds are generally shownwithout indicating a particular salt form.

The compounds of the present disclosure can be made using syntheticchemical techniques well known to those of skill in the art.

Example 1: Syntheses of Compounds 1-293

Compounds 1-293 may be prepared according to the methods described inSchemes 1-3 and according to the methods and procedures similar to thosedescribed for the synthesis of compound 120. Compound 120 wassynthesized according to the methods described below.

Synthetic Scheme for Compound 120

Experimental (Referring to Synthetic Scheme for Compound 120)

The solution of 4-Bromo-2-fluoro-benzaldehyde (1) (30.45 g, 150 mmol) inanhydrous dimethylformamide (214 ml) was cooled down to 0° C. To thiscold solution 11.05 g (157.5 mmol) of sodium thioacetate was added in 10portions in 3 min interval. After addition was complete the reactionmixture was stirred at the same temperature for 20 min then the coolingbath was removed and the reaction mixture was stirred for additional 30min. Water (250 ml) was added and the product was extracted with Ethylacetate (100 ml×2). Combined organic phase was washed with water (100ml) and brine (100 ml), dried over sodium sulfate, concentrated andpurified by flash chromatography (SiO₂ column, Heptane/Ethyl acetategradient) to obtain 34 g of (yield, 98%) of 2 as yellowish solid. MS(ESI) m/z [M+H]⁺; calcd for C₈H₈BrOS; 230.9, found 230.8.

To the solution of tert-Butane sulfonamide 2a (18.36 g, 150 mmol) and 2(34.66 g, 150 mmol) in anhydrous dichloromethane (150 ml) at roomtemperature under argon atmosphere was added cesium carbonate (50.35 g,150 mmol). The mixture was stirred at 40° C. for about 14 h. LCMS showedthe completion of the reaction. The reaction mixture was filteredthrough a pad of celite, concentrated and purified by flashchromatography (SiO₂ column, heptane/Ethyl acetate gradient) to obtain44 g (yield, 88%) of 3 as a yellowish solid. MS (ESI) m/z [M+H]⁺; calcdfor C₁₂H₁₇BrNOS₂; 333.9, found 333.9.

To the solution of 3 (30.08 g, 90 mmol) in 128 ml of anhydrousN—N′-dimethylformamide under argon atmosphere, activated zinc (10.29 g,157.5 mmol), LiCl (6.67 g, 157.5 mmol) and water (0.127 g, 7.11 mmol)were added, placed in water bath and stirred for 5 min. To this mixturewas added allyl bromide (19.05 g, 157.5 mmol) continued to stirvigorously for 1 h. LCMS showed complete consumption of 2. The reactionmixture was cooled down to 0° C., mixture of ethyl acetate (250 ml) and1 N aqueous hydrochloric acid (250 ml) were slowly was slowly added andvigorously stirred until the entire solid disappeared which tookapproximately 2 h. Organic phase was separated, aqueous phase wasextracted once more with ethyl acetate (100 ml). Combined organic phaseswere washed with water (150 ml) and brine (150 ml), dried over sodiumsulfate, concentrated and purified by flash chromatography (SiO₂ column,Heptane/Ethyl acetate gradient) to obtain 30.77 g (yield, 91%) of 4 as abrownish solid. MS (ESI) m/z [M+H]⁺, calcd for C₁₅H₂₃BrNOS₂; 376.0,found 376.0.

To the stirring solution of 4 (28 g, 74.4 mmol) in 31 ml of anhydrousTHF under argon atmosphere, the solution of 9-BBN (297.6 ml of 0.5 M inTHF, 148.8 mmol) was added dropwise over a period of time of 1 h and 30min. After completion of addition, the mixture was stirred for another 2h. LCMS showed complete consumption of 4. To this mixture iodoacrylate 5(prepared as described herein) was added and the mixture was thendegassed and purged with argon three times followed by addition ofPd(PPh₃)₄ (2.68 g, 2.35 mmol). The mixture was stirred under argon at55° C. for 2 h. LCMS showed compete consumption of the intermediate andformation of product. 50% of THF was evaporated, 250 ml of ethyl acetatewas added, and organic phase was separated. Aqueous phase was extractedwith another 250 ml of ethyl acetate. Combined organic phases was washedwith water (150 ml) and brine (150 ml), dried over sodium sulfate,concentrated and purified by flash chromatography (SiO₂ column,Heptane/Ethyl acetate gradient) to obtain 35 g (yield, 93%) of 6 as abrownish sticky solid. MS (ESI) m/z [M+H]⁺; calcd for C₂₂H₃₅BrNO₃S₂;504.1, found 504.2.

To the stirring solution of 6 (37.84 g, 75 mmol) in anhydrous dimethylacetamide (187 ml), anhydrous cesium carbonate (122.18 g, 375 mmol) wasadded and the mixture was vigorously stirred at 50° C. for about 17 h.LCMS showed the presence of traces of 6, the reaction mixture wasstirred for another 3 h at the same temperature. LCMS did not show anychange. Reaction mixture was cooled down, filtered through a plug ofcelite, the filter cake was washed with 100 ml of ethyl acetate. To thissolution 300 ml of water was added and product was extracted with ethylacetate (250 ml×2). Combined organic phases were washed with water (150ml) and brine (150 ml), dried over sodium sulfate, concentrated andpurified by flash chromatography (SiO₂ column, Heptane/Ethyl acetategradient) to obtain 28.3 g (yield 75%) of 7 as a yellowish solid. MS(ESI) m/z [M+H]⁺; calcd for C₂₂H₃₅BrNO₃S₂; 504.1, found 504.2.

To the stirring solution of 7 (29.76 g, 59 mmol) in anhydrous THF (147ml) under argon atmosphere, the solution of DIBAL (177 ml of 1 M soln inTHF, 177 mmol) was added dropwise (1 h 30 min). After completion ofaddition the reaction mixture was stirred for another 1 h. LCMS showedthe complete consumption of 7 and formation of 8. The mixture was cooleddown to 0° C., Rochelle's salt (100 ml 2N aqueous) was added dropwise(30 min, initial 10 ml was very slow) and left stirring at roomtemperature overnight. 300 ml of water was added organic phase wasseparated. Aqueous phase was extracted with 200 ml of ethyl acetate.Combined organic phases was washed with water (150 ml) and brine (150ml), dried over sodium sulfate, concentrated and purified by flashchromatography (SiO₂ column, Heptane/Ethyl acetate gradient) to obtain25.5 g (yield 97%) of 8 as a white solid. MS (ESI) m/z [M+H]⁺; calcd forC₁₈H₂₉BrNO₂S₂; 434.1, found 434.1.

To the stirring solution of 8 (20.33 g, 49 mmol) in anhydrous toluene(140 ml), at 0° C. temperature under argon atmosphere diphenylphosphoryl azide (18.8 g, 68.6 mmol) was added followed by dropwiseaddition of DBU (10.44 g, 68.6 mmol). Cooling bath was removed, stirredfor 30 min and then it was placed in 80° C. temperature oil bath andstirred for about 12 h. LCMS shows the completion of the reaction.Reaction mixture was cooled down to room temperature, 20 ml of water wasadded and the product was extracted by EtOAc (100 ml×2). Combinedorganic phases were washed with water (100 ml×2) and brine (100 nil),dried over sodium sulfate and concentrated to dryness to obtain 22.5 g(crude yield, 99.93%) of 9 as yellowish sticky solid. The crude wasapproximately 90% pure and was directly used for the next step withoutfurther purification. MS (ESI) m/z [M+H]⁺; calcd for C₁₈H₂₈BrN₄OS₂;459.1, found 459.1.

To the stirring solution of 8 (22.49 g, ˜ 49 mmol) in methanol (98 ml)aqueous HCl (12.25 ml 12 N, 147 mmol) was added dropwise and the mixturewas stirred at room temperature for 1 h LCMS showed complete removal oftert-butyl sulfonyl group. Evaporated to dryness, dissolved in THF (98ml), cooled down to 0° C., Cbz-Cl (10.03 g, 58.8 mmol) was addedfollowed by dropwise addition of K₂CO₃ solution (98 ml, 2N) and reactionmixture was stirred for 2 h. LCMS showed completion of Cbz protection.Organic phase was separated; aqueous phase was extracted with 100 ml ofethyl acetate. Combined organic phases was washed with water (100 ml)and brine (100 ml), dried over sodium sulfate, concentrated and purifiedby flash chromatography (SiO₂ column, Heptane/Ethyl acetate gradient) toobtain 22 g (yield 92%) of 10 as a white solid. MS (ESI) m/z [M+H]⁺;calcd for C₂₂H₂₆BrN₄O₂S; 489.1, found 489.1.

To the stirring solution of 10 (22 g, 45 mmol) in THF (277 ml),triphenylphosphine (17.7 g, 67.5 mmol) and water (23 ml) were added. Themixture was stirred at 55° C. for 4 h. LCMS showed complete reduction ofazide to amine. The reaction mixture was cooled down to 0° C., Bocanhydride (11.79 g, 54 mmol) was added, followed by addition of 85.7 mlof saturated sodium bicarbonate solution and stirred for 2 h. LCMSshowed complete consumption of intermediate amine and formation of 11.Organic phase was separated; aqueous phase was extracted with 100 ml ofethyl acetate. Combined organic phases was washed with brine (100 ml),dried over sodium sulfate, concentrated and purified by flashchromatography (SiO₂ column, Heptane/Ethyl acetate gradient) to obtain19.74 g (yield 78%) of 11 as a white solid. MS (EST) m/z [M+H]⁺; calcdfor C₂₇H₃₆BrN₂O₄S; 563.2, found 563.3

To the solution of 11 (19.72 g, 35 mmol) in anhydrous DMSO (175 ml),bispinacolatodiborane (17.95 g, 70 mmol), potassium acetate (12.14 g,122.5 mmol) and PdCl₂(dppf) CH₂Cl₂ (1.44 g, 1.75 mmol) were added. Themixture was degassed, purged with argon twice and stirred at 80° C. for13 h. LCMS showed complete consumption of 11 and formation of 12. Cooleddown to room temperature, 200 ml of water was added. Product wasextracted with ethyl acetate (150 ml×2). Combined organic phases werewashed with water (150 ml), 14% ammonium hydroxide (150 ml), water (150ml) and brine (150 ml). It was dried over sodium sulfate, concentratedand purified by flash silica gel chromatography (Heptane/Ethyl acetategradient) to obtain 19.70 g (yield, 93%) of 12 as a white solid. MS(ESI) m/z [M+H]⁺; calcd for C₃₃H₄₈BN₂OS; 611.3, found 611.4.

To the solution of 12 (19.7 g, 32.3 mmol) in methanol (470 ml), 117 mlof water was added. To this mixture were added 5-iodocytosine (10.82 g,45.22 mmol), and copper acetate monohydrate (6.44 g, 32.3 mmol) followedby tetramethylehtylenediamine (15 g, 129.2 mmol). The mixture wasstirred at room temperature under open air for 14 h. Formation of greenprecipitate was observed. LCMS showed presence of around 5% of 12. Itwas stirred for another 3 h. LCMS showed no change. Methanol wasevaporated. 400 ml of 28% NH₄OH and 400 ml of THF were added and stirredvigorously for 4 h until green precipitate was dissolved. Organic phasewas separated, aqueous phase was extracted with 100 ml of ethyl acetate.Combined organic phases was washed with water (100 ml), and brine (1000nil), dried over sodium sulfate and concentrated to dryness. The cruderesidue was dissolved in 235 ml of ethyl acetate, benzoic anhydride(10.33 g, 45.22 mmol) was added and the mixture was stirred at 80° C.for 2 h 30 min. LCMS showed completion of benzoylation of theintermediate amine. The reaction mixture was cooled down, washed withsaturated sodium bicarbonate solution (100 ml×2) and brine (100 ml),dried over sodium sulfate, concentrated and purified by flashchromatography (silica gel column, Heptane/Ethyl acetate gradient) toobtain 19.14 g (yield, 72%) of 13 as a white solid. MS (ESI) m/z [M+H]⁺;calcd for C₃₈H₄₃IN₅O₆S; 824.2, found 824.2. The solution of 13 (19.14 g,23.25 mmol) and alkyne (10.22 g, 25.6 mmol) in anhydrous DMF (155 ml)was degassed and purged with argon three times. To this solution wereadded N—N-diisopropylethylamine (12.14 g, 93 mmol) followed by Pd(PPh₃)₄(1.35 g, 1.16 mmol) and CuI (0.44 g, 2.32 mmol). The mixture was stirredat 70° C. for 12 h. LCMS showed completion of Sonogashira cyclization.The reaction mixture was cooled down to room temperature, 100 ml ofmethanol was added and stirred at 80° C. for 2 h 30 min. LCMS showedcompletion of debenzoylation and formation of 15. The reaction mixturewas cooled down to room temperature, methanol was evaporated, 200 ml ofwater was added. Product was extracted by ethyl acetate (100 ml×3).Combined organic phases was washed with water (100 ml), 14% ammoniumhydroxide (100 ml×2), water (100 ml) and brine (100 ml). The residue wasdried over sodium sulfate, concentrated and purified by flash columnchromatography (silica gel column, CH₂Cl₂/(90% CH₂Cl₂+9.8% methanol+0.2%NH₄OH)) to obtain 17.91 g (yield, 84%) of 15 as an orange solid. MS(ESI) m/z [M+H]⁺; calcd for C₅₄H₆₁ClFN₆O₇S; 991.4, found 991.5.

To the solution of 15 (20.82 g, 21 mmol) in 300 ml of methanol, HCl (73ml of 2N in water, 147 mmol) was added and stirred at 70° C. for 4 h.LCMS showed complete removal of Boc group. The reaction mixture wascooled down, 5 g of siliathiol and 5 g of activated charcoal were addedand the mixture was stirred overnight. Filtered through 10 g celite andevaporated to dryness in vacuo. The residue was dissolved in 50 ml ofmethanol and the product was precipitated by adding 500 ml of diethylether which was filtered and dried to obtain 15.77 g (yield, 81%) of 16as yellow solid. MS (ESI) m/z [M+1H]⁺; calcd for C₄₉H₅₂ClFN₆O₅S; 891.4,found 891.5.

To the solution of 16 (16.2 g, 17.5 mmol) in anhydrous methanol underargon atmosphere, ehtylacetimidate hydrochloride (4.35 g, 35 mmol) wasadded. The mixture was cooled down to about −10° C. andN—N-diisopropylethylarnine (9.10 g, 70 mmol) was added dropwise and leftstirring overnight without adding any more coolant. LCMS showedcompletion of amidination. Solvent was removed, residue was redissolvedin 62 ml of methanol, cooled down to 0° C., 125 ml of HBr solution (33%in acetic acid) was added and stirred for 10 min. Cooling bath wasremoved and stirred for another 2 h and 30 min at room temperature. LCMSshowed complete removal of Cbz groups. The solution was concentrated invacuo and purified by HPLC using C18 stationary phase (Column; Varian300 g Micros orb 60-8 C18, Irregular, Solvent A, water with 0.15% TFA,Solvent B, Methanol with 0.15% TFA, gradient 20-80% in 45 min, flow rate60 ml/min, diluent; 1:1 mixture of methanol and water with 0.15% TFA,injection volume: 10 ml, product elution starts at 28 min). Desiredfractions were concentrated to dryness after each run (which containsaround 420 mg of product), TFA was exchanged partially with HCl (6N aq.,10 ml) dissolved in ethanol. For combined batches, TFA was fullyexchanged with HCl (6N aq., 100 ml×2 with 100 ml of ethanol each time)and lyophilized to obtain 6.5 g (yield, 48%) of compound 120 as yellowsolid. ¹H NMR (300 MHz, D20): δ 8.42 (s, 1H), 7.71 (d, J=9 Hz, 2H), 7.50(s, 2H), 7.45 (d, J=12 Hz, 3H), 7.34 (d, J=9 Hz, 1H), 6.81 (s, 1H), 4.92(s, br, 1H), 3.81 (s, br, 1H), 3.53-3.37 (m, 2H), 2.70 (s, br, 2H),2.57-2.45 (m, 5H), 2.33-2.21 (m, 4H), 2.17-2.01 (s, br, 2H), 2.01-1.90(s, br, 4H), 1.83-1.70 (m, 4H), 0.97-0.84 (m, 1H), 0.71-0.53 (m, 2H).0.37-0.27 (m, 2H), MS (ESI) m/z [M+H]⁺; calcd for C₃₅H₄₄ClFN₇OS; 664.3,found 664.3.

Synthetic Scheme for Intermediate 5

Experimental (Referring to Synthetic Scheme for Intermediate 5)

To a solution of 57% hydrogen iodide (60 mL) in water (90 mL) was addedpropynoic acid (propiolic acid) 20 (20 g). The resulting mixture washeated at 50° C. for 24 h. The mixture was cooled to room temperatureand MTBE (100 mL) was added. The two layers were separated. The aqueouslayer was extracted with MTBE (100 mL). The combined organic phase waswashed with 2 M NaS₂O₃ (2×50 mL), 5% NaCl and dried over MgSO₄. Thesolution was filtered and concentrated to dryness to afford a beigesolid product 21 (49 g, 87%). To a solution of (Z)-3-iodo-acrylic acid21 (48 g) and t-BuOAc (140 g) in CH₂Cl₂ (144 mL, 3 vol.) was added TfOH(1.8 g). The solution was stirred at room temperature for 1 h. Thereaction was deemed complete (acid: HPLC area % 20.27%). The solutionwas neutralized with 2 M K₂CO₃ (242 mL). Heptane (144 mL) was added. Thetwo layers were separated. The aqueous layer was extracted with heptane(144 mL). The combined organic phase was washed with water (144 mL) anddried over MgSO₄. The solution was filtered and concentrated to drynessto afford an oil product 5 (49 g, 80%, HPLC area %: 98.22%).

Example 2—Antimicrobial Activity

The compounds of the present disclosure were tested for antimicrobialactivity. These data are presented in Table 2. The Compounds 1-293 wererun against Escherichia coli (E co/i) strain ATCC25922 and againstStaphylococcus aureus (S. aureus) 11540 strain using a standardmicrodilution assay to determine minimum inhibitory concentrations(MICs). The data is presented whereby a “+” indicates that the compoundhas an MIC value of 16 micrograms/mL or less and a “−” indicates thatthe compound has an MIC value greater than 16 micrograms/mL. It will berecognized by one skilled in the art that the compounds can be assessedagainst other bacterial organisms and that the presentation of data foractivity against Escherichia coli and Staphylococcus aureus areillustrative and in no way is intended to limit the scope of the presentdisclosure. The compounds of the present disclosure can be assayedagainst a range of other microorganisms depending upon the performanceactivity desired to be gathered. Furthermore, the “+” and “−”representation and the selection of a cutoff value of 16 micrograms/mLis also illustrative and in no way is intended to limit the scope of thepresent disclosure. For example, a “−” is not meant to indicate that thecompound necessarily lacks activity or utility, but rather that its MICvalue against the indicated microorganism is greater than 16micrograms/mL.

TABLE 2 MIC MIC # S. aureus E. coli 2 + + 3 + + 4 + + 6 + + 7 + + 8 + +9 + + 10 + + 11 + − 12 + + 13 − − 14 + + 15 + + 16 + + 17 + + 18 + +19 + + 20 + + 21 + + 22 + + 23 + + 24 + + 25 + + 26 + + 27 + + 28 + +29 + + 30 + + 31 + + 32 + + 33 + + 34 + + 35 + + 36 + + 37 + + 38 + +39 + + 40 + + 41 + + 42 + + 43 + + 44 + − 45 + + 46 + + 47 + + 48 + +49 + + 50 + + 51 + + 52 + + 53 + + 54 + + 55 + + 56 + + 57 + + 58 + +59 + + 60 + + 61 + + 62 + + 63 + + 64 + + 65 + + 66 − − 67 − − 68 + +69 + + 70 + + 71 + + 72 + + 73 + + 74 + + 75 + + 76 + + 77 + + 78 + +79 + + 80 + + 81 + + 82 + + 83 + + 84 + + 85 + + 86 + + 87 + + 88 + +89 + + 90 + + 91 + + 92 + + 93 + + 94 + + 95 + + 96 + + 97 + + 98 + +99 + + 100 + + 101 + + 102 + + 103 + + 104 + + 105 + + 106 + + 107 + +108 + + 109 + + 110 + + 111 + + 112 + + 113 + + 114 + + 115 + + 116 + +117 + + 118 + + 119 + + 120 + + 121 + + 122 + + 123 + + 124 + + 125 + +126 + + 127 + + 128 + + 129 + + 130 + + 131 + + 132 + + 133 + + 134 + +135 + + 136 + + 137 + + 138 + + 139 + + 140 + + 141 + + 142 + + 143 + +144 + + 145 + + 146 + + 147 + + 148 + + 149 + + 150 + + 151 + + 152 + +153 + + 154 + + 155 + + 156 + + 157 + + 158 + + 159 + + 160 + + 161 + +162 + + 163 + + 164 + + 165 + + 166 + + 167 + + 168 + + 169 + + 170 + +171 + + 172 + + 173 + + 174 + + 175 + + 176 + + 177 + + 178 + + 179 + +180 + + 181 + + 182 + + 183 + + 184 + + 185 + + 186 + + 187 + + 188 + +189 + + 190 + + 191 + + 192 + + 193 + + 194 + + 195 + + 196 + + 197 + +198 + + 199 + + 200 + + 201 + + 202 + + 203 + + 204 + + 205 + + 206 + +207 + + 208 + + 209 + + 210 + + 211 + + 212 + + 213 + + 214 + + 215 + +216 + + 217 + + 218 + + 219 + + 220 + + 221 + + 222 + + 223 + + 224 + +225 + + 226 + + 227 + + 228 + + 229 + + 230 + + 231 + + 232 + + 233 + +234 + + 235 + + 236 + + 237 + + 238 + + 239 + + 240 + + 241 + + 242 + +243 + + 244 + + 245 + + 246 + + 247 + + 248 + + 249 + + 250 + + 251 + +252 + + 253 + + 254 + + 255 + + 256 + + 257 + + 258 + + 259 + + 260 + +261 + + 262 + + 263 + + 264 + + 265 + + 266 + + 267 + + 268 + + 269 + +270 + + 271 + + 272 + + 273 + + 274 + + 275 + + 276 + + 277 + + 278 + +279 + + 280 + + 281 + + 282 + + 283 + + 284 + + 285 + + 286 + + 287 + +288 + + 289 + + 290 + + 291 + + 292 + + 293 + + 317 + + 318 + + 319 + +320 + + 321 + + 322 + + 323 + + 325 + + 326 + + 327 + + 328 + + 329 + +330 + + 331 + + 332 + + 333 + + 334 + + 335 + + 336 + + 337 + + 338 + +339 + + 340 + + 341 + + 342 + + 343 + + 344 + + 346 + + 347 + + 348 + +349 + + 350 + + 351 + + 352 + + 353 + + 355 + + 356 + + 357 + + 358 + +360 + + 362 + + 363 + + 364 + + 365 + + 366 + + 369 + + 370 + + 377 + +

Example 3—Rat Five Day Safety Study

The compounds of the present disclosure were tested for safety in amulti-day dosing study in rat. Key parameters that were monitored arebodyweight gain and hematological changes, particularly changes inreticulocyte counts. Male Sprague-Dawley (CD) juvenile rats werereceived from Charles River with double jugular vein catheters. For eachcompound, n=5. Doses for each compound were variable and were chosen tobe at or near the maximum-tolerated dose in rat and were administeredonce daily via slow intravenous infusion at 10 mg/kg for 10 minutes, for5 days. Bodyweights were recorded daily for the first 5 days (during thedosing period), then 2 to 3 times per week thereafter. Blood wascollected via a jugular vein catheter into EDTA anti-coagulated tubesfor complete blood counts (CBC) on Days 0 (baseline), 3 and 7. On Day22, blood was drawn via a cardiac puncture into EDTA coated tubes forfinal CBC, and serum separator tubes for the complete clinical chemistryprofile. The blood that was collected into serum separator tubes wasallowed to clot at room temperature for approximately 30 minutes, spunin a centrifuge at 2000 rpm, and the resulting serum was aliquoted. Allsamples were sent on wet ice to Charles River Labs for analysis. Thedata is presented in Table 3 whereby a “+” in “BW result” indicates thatthe rat exhibited a weight gain of 20% or more and a “−” indicates thatthe rat exhibited a weight gain of less than 20%. Furthermore, a “+” in“Hematology result” indicates indicates that the rat exhibited areticulocyte count change of 65% or less and a “−” indicates indicatesthat the rat exhibited a reticulocyte count change of greater than 65%.

TABLE 3 Compound No. BW Result Hematology Result 23 + + 36 − − 36 + −50 + + 110 − − 117 − + 119 − − 120 + + 123 + + 127 + + 152 + + 162 − −182 − − 190 − − 191 + + 196 + + 199 + − 200 + − 249 + + 254 + + 264 + +290 + + 317 − − 341 + + 360 + +

Example 4—Activity of Pyrrolocytosine Protein Synthesis InhibitorsAgainst Multiresistant Gram-Negative Bacteria

Four compounds, including Compound Nos. 120 and 162 of the presentapplication (RX-04B and RX-04C, respectively) were tested against (i)multiresistant Enterobacteriaceae and Acinetobacter with carbapenemases;(ii) Enterobacteriaceae with MCR-1; and (iii) P. aeruginosa with alteredefflux (see Tables 4 and 5). In this case, MCR-1 is relevant because itsactivity reduces the negative charge of lipopolysaccharides, potentiallyaffecting binding of poly-basic molecules such as the compounds testedherein, as well as polymyxins.

TABLE 4 Compounds Tested

RX-04A

RX-04B

RX-04C

RX-04D

TABLE 5 Test Panel Resistance mechanism/phenotype* Carbapenem +cephalosporin E. coli DH10B susceptible Low Normal Raised DH10B mcr-1Species controls KPC SME MBL OXA-48 OXA-23 efflux efflux efflux MCR-1recipient transformant E. coli 5 5 — 5 5 — — — — 3 1 1 S. enterica — — —— — — — — — 11 — — K. pneumoniae 5 5 — 5 5 — — — — — — — Enterobacterspp. 4 2 — 1 1 — — — — — — — S. marcescens 2 — 1 — 1 — — — — — — — P.aeruginosa — — — 5 — — 5 5 5 — — — A. baumannii 5 — — — — 5 — — — — — —E. coli ATCC 25922 and P. aeruginosa ATCC 27853 were controls throughout*numbers in the table refer to the number of each species that exhibitthe particular resistance/genotype.

MICs of the four tested compounds and comparators (amikacin, cefepime,colistin, meropenem and tigecyline) were determined by CLSI brothmicrodilution using pre-prepared plates (Trek Diagnostic Systems) (CLSIApproved Standard M7-A10). Carbapenemase and mcr-1 genes were detectedby PCR or sequencing. Efflux levels in P. aeruginosa isolates wereinferred by interpretive reading of antibiogram data.

MICs for the 68 Enterobacteriaceae were unimodal, with peaks at 1 mg/Lfor analogues RX-04A and RX-04B and 2 mg/L for RX-04C and RX-04D (FIG.1). For RX-04A, the most active of the tested analogues, 67/68 (>98%)MICs were 0.25-2 mg/L. For all of the tested compounds, MICs were lowestfor E. coli and highest for S. marcescens (MICs from 8 to greater than16 mg/L were seen for one Serratia).

MICs of RX-04A for 35/36 (97%) of CPE were within 4-fold of the MIC forE. coli ATCC 25922 (FIG. 2). MTC differentials for analogues RX-04B-Dwere similarly small. MICs of RX-04A for all MCR-1 isolates (n=14) werewithin 2-fold of that for E. coli ATCC 25922 (FIG. 3). MIC differentialsfor analogues RX-04B-D were similarly small. Acquisition of mcr-1 didnot raise RX-04 MICs for E. coli DH10B (Table 6).

TABLE 6 MICs of RX04-A-D and colistin for E. coli DH10B and its mcr-1transformant MIC (mg/L) Strain RX-04A RX-04B RX-04C RX-04D COL DH10BRecipient 0.25 0.5 0.5 1 0.25 MCR-1 Transformant 0.25 0.5 0.5 1 4

MIC distributions of RX-04 analogues A-C straddled 1-8 mg/L for the 10A. baumannii. RX-04A had the lowest MICs, with 7/10 values from 1-2mg/L, D was the least active analogue (FIG. 4) MICs for A. baumanniiwith OXA-23 carbapenemases were mostly higher thancarbapenem-susceptible isolates, but numbers were small and 3/5 OXA-23isolates belonged to the same lineage (International Clone II; the other2 were unique pulsotypes). RX-04A again was the most active analogueagainst P. aeruginosa isolates, with MICs from 1-4 mg/L for 19/20 (95%)isolates. Almost half (48%) of the MICs were ≥16 mg/L for analogues Cand D (FIG. 5). MICs of all analogues tended to be higher for P.aeruginosa with ‘normal’ vs. low efflux, but not further raised forthose with elevated efflux.

The four analogues had broad activity against Enterobacteriaceae andnon-fermenters. RX-04A was the most active analogue with MICs mostly 1-2mg/L for Enterobacteriaceae and A. baumannii and 1-4 mg/L for P.aeruginosa. Among Enterobacteriaceae, E. coli was the most susceptiblespecies and S. marcescens the least susceptible. MICs for carbapenemaseproducers and MCR-1 isolates were only 2-4-fold above a highlysusceptible control. Acquisition of MCR-1 did not affect susceptibilityto these basic molecules, despite affective surface charge. RX-04A MICswere not raised in P. aeruginosa isolates with elevated efflux. MICswere slightly raised against multiresistant A. baumannii.Pyrrolocytosines showed promising activity against this challengingcollection of multiresistant Gram-negative bacteria.

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

EQUIVALENTS

The disclosure can be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting on the disclosure described herein. Scope of thedisclosure is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

1. (canceled)
 2. A compound of Formula (II):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein: R₁ is selected from the group consistingof H and halo; R₂ is selected from the group consisting of H, halo, C₁₋₆alkyl, C₁₋₄ haloalkyl, and OR^(a1); R³ is selected from the groupconsisting of H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, and C(O)OR^(a1); W isselected from the group consisting of N and CR₄; R₄ is selected from thegroup consisting of H, halo, OR^(a2), SR^(a2), 5-6 memberedheterocycloalkyl, S(O)₂R^(b2), C₁₋₆ alkyl, and C₂₋₆ alkenyl, wherein theC₁₋₆ alkyl is optionally substituted with a substituent selected fromOR^(a2); R₅ is selected from the group consisting of H, halo, C₁₋₆alkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆ alkyl is optionallysubstituted with a substituent selected from OR^(a2); R₆ is selectedfrom the group consisting of H, C₁₋₆ alkyl, C₃₋₅ cycloalkyl, and C₂₋₆alkenyl, wherein the C₁₋₆ alkyl is optionally substituted with asubstituent selected from the group consisting of OR^(a3), SR^(a3), andNR^(c3)R^(d3); R_(7A) is selected from the group consisting of H, C₁₋₆alkyl, C₁₋₄ haloalkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆ alkyl isoptionally substituted with a substituent selected from the groupconsisting of OR^(a3) and SR^(a3); R_(7B) is H; or R_(7A) and R_(7B)together with the carbon atom to which they are attached form a groupselected from the group consisting of oxo, and C₃₋₆ cycloalkyl; or R₆and R_(7A) together with the carbon atoms to which they are attached andthe X atom connecting the two carbon atoms form a 5- to 6-memberedheterocycloalkyl containing 1-3 heteroatoms selected from N, O and S; Xis selected from the group consisting of O and NR₈; R₈ is selected fromthe group consisting of H, C₁₋₆ alkyl, and C₁₋₄ haloalkyl, wherein theC₁₋₆ alkyl is optionally substituted with R_(8A); R_(8A) is selectedfrom the group consisting of 5- to 6-membered heteroaryl, and OR^(a3)wherein the 5- to 6-membered heteroaryl is optionally substituted withone or two C₁₋₆ alkyl; R₉ is selected from the group consisting of H,C₂₋₄ alkenyl, C₁₋₄ haloalkyl and C₁₋₄ alkyl optionally substituted witha substituent selected from the group consisting of amino, C₁₋₄ alkoxy,C₃₋₅ cycloalkyl, and 3- to 6-membered heterocycloalkyl; R₁₀ is selectedfrom the group consisting of H and C₂₋₆ alkenyl; R_(A) is selected fromthe group consisting of H and C₁₋₆ alkyl; L is selected from the groupconsisting of C₁₋₆ alkyl and C₂₋₆ alkenyl, wherein the C₁₋₆ alkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, OR^(a4), and SR^(a4); R₁₁ is selected from the groupconsisting of H, C₁₋₆ alkyl, C₃₋₅ cycloalkyl, C₁₋₄ haloalkyl, and C₂₋₆alkenyl, wherein the C₁₋₆ alkyl is optionally substituted with 1, 2, or3 substituents independently selected from the group consisting of CN,OR^(a5), SR^(a5), C(O)NR^(c5)R^(d5), NR^(c5)R^(d5), and S(O)₂R^(b5); R₁₂is selected from the group consisting of H and C₁₋₆ alkyl; or R₁₁ andR₁₂ together with the carbon atom to which they are attached form a C₃₋₅cycloalkyl; R₁₃ is selected from the group consisting of H, halo, andC₁₋₆ alkyl; R₁₄ is selected from the group consisting of H, halo, andC₁₋₆ alkyl; and R_(B) is selected from the group consisting of H andC(═NR^(e5))R^(b5); or R₁₁ and R_(B) together with the carbon atom towhich R₁₁ is attached and the nitrogen atom to which R_(B) is attachedform a 5- to 6-membered heterocycloalkyl containing 1-3 heteroatomsselected from the group consisting of N, O and S, wherein the 5- to6-membered heterocycloalkyl is optionally substituted with oxo; eachR^(a1), R^(a2), R^(a3), R^(a4), R^(a5), R^(b2), R^(b5), R^(c3), R^(d3),R^(c5), and R^(d5) is independently selected from the group consistingof H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, and 5-membered heteroaryl; and R^(e5)is selected from the group consisting of H and C₁₋₄ alkyl.
 3. Thecompound of claim 2, wherein R₁ is halo; or R₁ is selected from thegroup consisting of H and fluoro; or R₁ is fluoro; or R₁ is C₁₋₄ alkoxy;or R₁ is methoxy. 4-7. (canceled)
 8. The compound of claim 2, wherein R₂is selected from the group consisting of H, halo, C₁₋₄ haloalkyl, andC₁₋₄ haloalkoxy; or R₂ is selected from the group consisting of halo,C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy; or R₂ is selected from the groupconsisting of H, trifluoromethoxy, trifluoromethyl and chloro; or R₂ isselected from the group consisting of trifluoromethoxy, trifluoromethyland chloro. 9-11. (canceled)
 12. The compound of claim 2, wherein R₁ ishalo and R₂ is halo; or R₁ is fluoro and R₂ is chloro.
 13. (canceled)14. The compound of claim 2, wherein R₃ is selected from the groupconsisting of H, C₁₋₄ haloalkyl, and C(O)OR^(a1); or R₃ is selected fromthe group consisting of H, C₁₋₄ haloalkyl, and C(O)C₁₋₄ alkoxy; or R₃ isselected from the group consisting of H, trifluoromethyl, andC(═O)(methoxy); or R₃ is H. 15-17. (canceled)
 18. The compound of claim2, wherein W is N; or W is CR₄.
 19. (canceled)
 20. The compound of claim2, wherein R₄ is selected from the group consisting of H, halo, C₁₋₆alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, S(C₁₋₄ alkyl), 6-memberedheterocycloalkyl, and S(O)₂ C₁₋₄ alkyl; or R₄ is selected from the groupconsisting of halo, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, S(C₁₋₄alkyl), 6-membered heterocycloalkyl, and S(O)₂ C₁₋₄ alkyl; or R₄ isselected from the group consisting of H, fluoro, chloro, methylthio,methoxy, methyl, S(═O)₂(methyl), trifluoromethoxy, and N-morpholino; orR₄ is selected from the group consisting of fluoro, chloro, methylthio,methoxy, methyl, S(═O)₂(methyl), trifluoromethoxy, and N-morpholino; orR₄ is H. 21-24. (canceled)
 25. The compound of claim 2, wherein R₅ ishalo; or R₅ is selected from the group consisting of H and F; or R₅ isF; or R₅ is H. 26-28. (canceled)
 29. The compound of claim 2, wherein R₅is halo and R₄ is selected from the group consisting of halo, S(C₁₋₄alkyl), and 6-membered heterocycloalkyl; or R₅ is halo, and R₄ is S(C₁₋₄alkyl); or R₅ is fluoro and R₄ is selected from the group consisting offluoro, methylthio, and N-morpholino; or R₅ is fluoro and R₄ ismethylthio. 30-32. (canceled)
 33. The compound of claim 2, wherein R₆ isselected from the group consisting of H, C₃₋₅ cycloalkyl, C₂₋₆ alkenyl,C₁₋₆ alkyl optionally substituted with a substituent selected from thegroup consisting of hydroxyl, C₁₋₄ alkoxy, S(C₁₋₄ alkyl), amino, andNH(5-membered heteroaryl); or R₆ is selected from the group consistingof C₃₋₅ cycloalkyl, C₂₋₆ alkenyl, C₁₋₆ alkyl optionally substituted witha substituent selected from hydroxyl, C₁₋₄ alkoxy, S(C₁₋₄ alkyl), amino,and NH(5-membered heteroaryl); or R₆ is selected from the groupconsisting of H, cyclopropyl, ethenyl, aminomethyl, hydroxymethyl,CH₂NH-imidazole, methylthiomethyl, and methoxymethyl; or R₆ is selectedfrom the group consisting of cyclopropyl, ethenyl, aminomethyl,hydroxymethyl, CH₂NH-imidazole, methylthiomethyl, and methoxymethyl; orR₆ is H. 34-37. (canceled)
 38. The compound of claim 2, wherein R_(7A)is selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, and C₂₋₆ alkenyl; or R_(7A) is selected from thegroup consisting of C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, andC₂₋₆ alkenyl; or R_(7A) is selected from the group consisting of H,methyl, trifluoromethyl, hydroxymethyl, difluoromethyl, and ethenyl; orR_(7A) is selected from the group consisting of methyl, trifluoromethyl,hydroxymethyl, difluoromethyl, and ethenyl; or R_(7A) is H. 39-42.(canceled)
 43. The compound of claim 2, wherein R_(7A) and R_(7B)together with the carbon atom to which they are attached form oxo; orR_(7A) and R_(7B) together with the carbon atom to which they areattached form C₃₋₆ cyclopropyl.
 44. (canceled)
 45. The compound of claim2, wherein R₆ is selected from the group consisting of C₂₋₆ alkenyl,C₁₋₆ hydroxyalkyl, and C₁₋₆ alkylene-NH(5-membered heteroaryl), andR_(7A) is C₁₋₆ alkyl; or R₆ is selected from the group consisting ofethenyl, hydroxymethyl, and CH₂NH-imidazole, and R_(7A) is C₁₋₆ alkyl;or R₆ is H and R_(7A) is C₁₋₆ alkyl, or R₆ is H and R_(7A) is methyl.46-48. (canceled)
 49. The compound of claim 2, wherein R₆ is H andR_(7A) is methyl, and the carbon atom to which R_(7A) is attached is in(S) configuration according to Cahn-Ingold-Prelog nomenclature.
 50. Thecompound of claim 2, wherein R₆ is H and R_(7A) is methyl, and thecarbon atom to which R_(7A) is attached is in (R) configurationaccording to Cahn-Ingold-Prelog nomenclature.
 51. The compound of claim2, wherein R₆ and R_(7A) together with the carbon atoms to which theyare attached and the X atom connecting the two carbon atoms form a6-membered heterocycloalkyl containing 1-3 heteroatoms selected from thegroup consisting of N, O and S; or R₆ and R_(7A) together with thecarbon atoms to which they are attached and the X atom connecting thetwo carbon atoms form a ring of any one of the following formulae:

or R₆ and R_(7A) together with the carbon atoms to which they areattached and the X atom connecting the two carbon atoms form a ring ofthe following formulae:

wherein x indicates a point of attachment to the ring containing the Watom and substituted with R₅; or R₆ and R_(7A) together with the carbonatoms to which they are attached and the X atom connecting the twocarbon atoms form a ring of any one of the following formulae:

or R₆ and R_(7A) together with the carbon atoms to which they areattached and the X atom connecting the two carbon atoms form a ring offormula:

wherein x indicates a point of attachment to the ring containing the Watom and substituted with R₅; or R₆ and R_(7A) together with the carbonatoms to which they are attached and the X atom connecting the twocarbon atoms form a ring of any one of the following formulae:

wherein x indicates a point of attachment to the ring containing the Watom and substituted with R₅; or R₆ and R_(7A) together with the carbonatoms to which they are attached and the X atom connecting the twocarbon atoms form a ring of any one of the following formulae:

wherein x indicates a point of attachment to the ring containing the Watom and substituted with R₅. 52-57. (canceled)
 58. The compound ofclaim 2, wherein X is O; or X is NR₈.
 59. (canceled)
 60. The compound ofclaim 2, wherein R₈ is selected from the group consisting of H, C₁₋₆alkyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₆ alkyl substituted withC₁₋₆ alkoxy, and C₁₋₆ alkyl substituted with 5- to 6-memberedheteroaryl, wherein the 5- to 6-membered heteroaryl is optionallysubstituted with 1, or 2 C₁₋₆ alkyl; or R₈ is selected from the groupconsisting of H, methyl, 3-fluoropropyl, 2-methoxyethyl,3-hydroxypropyl, 2-(pyridinyl)ethyl, 2-(imidazolyl)ethyl,(imidazolyl)methyl, and (oxazolyl)methyl, wherein each pyridinyl,imidazolyl, and oxazolyl is optionally substituted with 1 or 2 methyl;or R₈ is selected from the group consisting of any one of the followingformulae:

or R₈ is selected from the group consisting of methyl, 3-fluoropropyl,2-methoxyethyl, and 3-hydroxypropyl; or R₈ is H. 61-64. (canceled) 65.The compound of claim 2, wherein R₉ is H; or R₉ is C₁₋₆ alkyl; or R₉ ismethyl. 66-117. (canceled)